IRAK inhibitor and preparation method therefor and use thereof

Abstract

Disclosed is a compound represented by formula I, a stereoisomer, racemate, tautomer, isotopic label, prodrug thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising same, a preparation method therefor, and medical use thereof. The structure is as shown in formula I.

Description

SPECIFICATION IRAK INHIBITOR AND PREPARATION METHOD THEREFOR AND USE THEREOF The present application claims priority to Chinese Patent Application No. 201910906833.7 filed with China National Intellectual Property Administration on Sep. 24, 2019 and entitled "IRAK INHIBITOR AND PREPARATION METHOD THEREFOR AND USE THEREOF", which is incorporated herein by reference in its entirety, TECHNICAL FIELD The present invention relates to the field of pharmaceutical chemistry, particularly to a compound suitable for treatment of cancer and inflammatory diseases related to interleukin-1 receptor-associated kinase (IRAK), and more particularly to a compound for regulating a function of IRAK-4. BACKGROUND Interleukin-1 receptor-associated kinase (IRAK) family are intracellular serine-threonine protein kinases, including: IRAKI, IRAK2, IRAK-M and IRAK4. A common feature of these four members is the typical N-terminal death domain that mediates the interaction between the MyD88 family adapter and the central kinase domain, wherein IRAK1 and IRAK4 have activity. IRAK4 is a key factor downstream of the Toll-like receptor (TLR ) / interleukin-1 receptor (IL-1R)-mediated inflammatory signaling pathway. When the binding of ligand to a pathogen-specific molecule (e.g., lipopolysaccharide, polypeptide and viral DNA) recognized by the extracellular portion of TLR, the intracellular portion recruits MyD88 and other factors to form complexes and initiate IRAK1 autophosphorylation, thereby activating downstream serine-threonine kinase TAKI, promoting NF-«B and MAPK signaling pathways, producing proinflammatory cytokines, chemokines and destructive enzymes, and ultimately leading to inflammatory responses that mediate innate immunity. IL-1R is involved in host defense and hematopoiesis and serves as a bridge connecting the innate immunity and acquired immunity, (Flannery, et, al, Biochem, Pharmacol., 2010, 80 cells and mediate the inflammation in RA T / B and TNF-a. Studies have shown that IRAK4 inhibitors can effectively block the production of the proinflammatory cytokine tumor necrosis factor (TNF) in LPS or CpG-induced human leukocytes; in mice with collagen-induced arthritis, IRAK4 inhibitors can significantly inhibit the release of TNF, thereby controlling disease progression; in mice with MyD88-dependent inflammatory gout, IRAK4 inhibitors are able to dose-dependently block leukocyte infiltration (Priscilla N, et. al, J. Exp. Med., 2015, 13 (212):2189-2201). Therefore, it is believed that the excessive activation of IRAK4-dependent TLR / IL-1R signaling pathway is closely related to the development and progression of rheumatoid arthritis. It has been confirmed in various studies that IRAK4 activation is closely related to the onset and progression of diseases such as tumors, gout, systemic lupus erythematosus, multiple sclerosis, metabolic syndrome, atherosclerosis, myocardial infarction, sepsis, inflammatory bowel disease, asthma, and allergy (Chaudhary D, et. al., J, Med, Chem. 2015, 58 (1):96-110). SUMMARY In order to solve the problems in the prior art, the present invention provides a compound of formula I or a stereoisomer, a racemate, a tautomer, an isotopically labeled compound, a prodrug or a pharmaceutically acceptable salt thereof, A Oo rad (Rn =N R,-W Formula I one, two or more R: According to one of the present the "(Ci-Ciz)aliphatic hydrocarbyl optionally comprising one, two or more heteroatoms" may be selected from (Ci-Ciz)aliphatic hydrocarbyloxy, (C1-Ciz)aliphatic hydrocarbylthio, (C1-Ce)aliphatic hydrocarbyloxy(Ci-Cs)aliphatic hydrocarbyl, (Ci-Cs)aliphatic hydrocarbylthio(Ci-Ce)aliphatic hydrocarbyl, ~~ N-(Ci-Cs)aliphatic ~~ hydrocarbylamino(Ci-Ce)aliphatic = hydrocarbyl, ~~ and N,N-di-(C1-Cs)aliphatic hydrocarbylamino(Ci-Ce)aliphatic hydrocarbyl; the "5-14 membered heteroaryl or 5-12 membered heterocyclyl containing at least one N" refers that the heteroaryl or heterocyclyl contains at least one nitrogen atom, and further may contain other one or more heteroatoms selected from N, O and S, for example, selected from pyridine, pyrrole, piperidine and tetrahydropyrrole; the (Ci-Ciz)aliphatic hydrocarbyl may be selected from (Ci-Ciz)alkyl, (C2-Ciz)alkenyl and (C2-Cr2)alkynyl, and preferably, the (Ci-Ci)aliphatic hydrocarbyl may be selected from (C1-Ce)alkyl, (C2-Ce)alkenyl and (C2-Cs)alkynyl; the "halogen" is selected from F, Cl, Br and I; and the "Cs.12 cycloalkyl" may be selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. According to one embodiment of the present invention, the Ri, R2 and R3 may be each independently selected from the following groups optionally substituted with one, two or more R: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 1-ethylethenyl, 1-methyl-2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 1-hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl, 1-hexynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxyl, propoxy, butoxy, pentyloxy, methoxymethyl, ethoxylmethyl, propoxymethyl, methoxyethyl, ethoxylethyl, propoxyethyl, methoxypropyl, ethoxylpropyl, propoxypropyl, N-methylaminomethyl, N-methylaminoethyl, N-ethylaminoethyl, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, amino, N,N-dimethylamino, N,N-diethylamino, tetrahydropyrrolyl, piperidinyl, pyridyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, =o 4< 24 OH HOKE ONL 0 Len KX CN | $F 3x OH VOH 3 Y—OH ya 4 Fe LF 15 WOH bl yon oh ar AC + F F F vo OH = Xo 7 \ << N "oe = N N OH | OH I WE NA I $— NL | { and the ndn denotes the connection site of the group. According to an embodiment of the present invention, in the compound of formula I or the stereoisomer, the racemate, the tautomer, the isotopically labeled compound, the prodrug or the pharmaceutically acceptable salt thereof, the compound of formula I may be selected from the following structures of formula Ia, formula Ib, formula Ic, formula Id and formula Ie: 2. / Ay Oo Z Oo Rall NF Roh NAY N-R4 O~ HN O~ HN (Ryn R,-W N Ry-W N formula Ia formula Ib AS N™ °F 3 (Ral KAP N-R4 O~ HN = Ri O~ HN _ =, N =, ) R,-W N R,-W N formula Ic formula Id x1) 0 +2 Ry N">¢ N-R4 O HN _ = A R,-W N formula Ie in the formula Ia, formula Ib, formula Ic, formula Id and formula Ie, Ri, Ra, Rs, m, n and W are as defined in formula I. According to an embodiment of the present invention, in the compound of formula I or the stereoisomer, the racemate, the tautomer, the isotopically labeled compound, the prodrug or the pharmaceutically acceptable salt thereof, the compound of formula I may be selected from the following structures: OH 001 002 “1 N+ 0 & HN. = - (1 J 001 “I " H SJ OR" 002 wei Woe 7 | Z > HN = OH & uN = OH SE OR" Ie OR 003 004 A AN ua ue @ Q Sy “he - HN 2 Oil - HN 2 OH JE Da J (Hs 005 008 AN pn LI, yA ) 7 _ V i “C Po SO Tr . A oo 0 07 v 008 So ” bo JK wl Vi 008 I o10 Lhe 3 OH NPE Pe ~ <N N I oto ON 011 p12 4 < | § H © HN. = OH SJR OR boo ON Cl Sr © HN. = OH JOR ! on 2 7 | o Z o ” H "HI TT yon” I yo 013 014 PN A 015 016 ~ ae Loe & HN ) JE 016 AN Zz “7 & HN. ~ HN a Torr rm CR 015 016 2N A Yoh oH 017 018 016 7 "HN H JR 018 ~ cd SA & HN. 00 017 AN Yeo JT Yeon AA y i Lon a AEM 019 - 020 021 022 * 018 4 “She & - C - = 4 vO 021 ¥ 3 - Shee - HN I 022 7 Z ” HN "HI POR en IRM 023 024 AN 2 Lhe Sr & HN & Hn. Bi Oe Im 025 0268 Ph AN rH ee i DCE en, ASR 027 028 AN AN 027 028 “N <Q I” HN. = of "HI = EO, am 029 030 ~y a AO 3 oR wv 031 Vo 02 2 | =~ Y 2 Le "HI & HN TOO ME ve 033 v v Y on & HN. , 5 A Vv 03 - ) 034 @ =z "HN - H TORO, hE 1 035 1 036 CY ~ 1 035 I 036 “3 Q Che Se "HN, a. SR Hw IDE 037 038 SOK AY AN 040 039 QL Pr TE SN ¥ HN = wl ye < L) Sproe ANA 041 042 Zl “ © HN, "HI = Aw KE 04s YL 7 re 044 ~ 043 044 7 | Z FA, AAO < § HN OH whe AJR CR 045 04s pe AN vv 047 048 N* | & un z a. PSD MULL CSNY 1 vo N Vv 049 050 v 049 050 3 z A whee ” HN = OH "HN = IIR IR 051 - 052 7 We i & HN = OH rl Dh nea 053 Vv 054 ” HN. I ve 054 » B 033 wv 054 Go Cl. & H F ¥ HN. JT HA SIEM I oss 1 oss Z 2, ~ “1 z TRO ome AY A 1 oss boost Io Loo > 0 - SN v HN OH I & un = o SIE wk Po + 1 058 FY ay Ymon I 059 Toso A 2 - HN HA oa ler 081 062 AN N 081 062 2 “Pr Lhe & HN HNN LEM ren Fey 083 re AN ) cd > | 0 SR mf 084 063 © 084 7 We Loe Td mn = 0 y i SOR on © Ey 065 066 ANAS RN 21 2 ~ HN. H J 066 ANG 065 B 066 CL Cl 0 & un > F 5 HN. CJ pen TYR 087 068 FE bom 2 Thon 088 Yoh 069 070 “I "HI J 069 AN ol KE 070 AN oH Cl FO a 2 ! & HN H = Nine TT 72 069 2 YA ” HN. OR 071 a 071 or2 0 TRE v = allo oH 7 V Ya Cl, 7 ve 075 4 ye I Yoh o 075 * 078 cd SA Le " HN. / owed Jon té XX V —N To SN 7 & | 0 CRE 080 . 077 oy 078 7 Zz Cp Py * HN, - HN 00 Yoon JE ore "om a PY 081 ' os2 A 079 © 080 Z F 5 8 Q & HN HN Wy = Nie OH "HN = SR (> Xx 081 082 wih H rH = LR 082 oH 2 Ae ” HN. LT a 7 We Tb mn on Toss AA) ' 083 1 oss Zz | 2 * HN, = - H JR O% 085 086 AN me oes - 086 Z ~y 2 0 YT. . ROR ITE 087 088 AN AN 087 088 Ae AA FN = OH "4 = DORs, LR 08g 080 ANA ne 4 Hi 5 Qe) = yy ARR mr ] - ] ~ 082 091 _ 082 Nar Ry i» ie ad Po a & uN ~XR (Oe OE ~ 094 ANG 095 oo 096 093 i” 084 “lee z FY + Ah = Nine OH & HN. TI x 095 v ", aa \vd ) } av vane 3 9 v oo * IIRC Y ‘ eT 8 ou ” HN. 099 v 100 Se LI odo PERL SE 7 o TORO ORM O8 vo W v 101 v 102 7 CA z | S, 0 & HN. = a F’ o HN. 103 Ta 103 “1 rH = OH SJ I 1038 7 5) 0 wl Tb Wh yh i’ JOE (Ong ! 108 AN 107 ’ 108 ! 108 S108 Si ° oN ry LS 7 bod = OH 1 2) SIT SOR 107 AN wa > | 0 SLI o LEO | 108 ON iy 109 110 | & AE OX 110 NG AJ] i” 109 TU me 7 7 "HN, HN = OH mM 12 7 Se & uN _ i JE Do (J 13 A 2] on A " HN = C0 nd 1a ~ - 13 Nd 1a 2 " HN = OH N* Ne G9 Bo & "“ & ey = us Tn AY. A ~- 17 w= 448 1s N= qe See Le 4 uN ” OH 4 uN, In or nee (OD HO. J oe & "7? Cl 8 2). oy She hy N* 3 AO & HN bd H TEX em oC 19 ‘ Ch 120 jal Oo AN OH Su cd H 4 HN = wl MN SN Ny J 122 A > 1 ak SN 1m EH ] 4 > 0 ZZ N* so & uN - y CE 2 / N % N | 4 121 x 12 LL 7 SAD " os) NI 121 XS 122 7 ] Zz “he Lhe HN AN oH "HN ey Ds JOR 123 < 124 x 123 NO 124 @ 2 > HN = OH & uN OR Bon \ 125 L 126 Loe Ad & y AJR ron OR 2 127 2 128 1 29 rr 130 127 128 @ 2 AA Lhe - HN, "HN ASE on OE 120 = 130 ANG @ - Lhe "HN OH JE So 130 ON oH 131 Nn 432 129 iz Ade & HN JEM J 131 AY 2] AA & «OH = J ga Pv HoH 133 N=! 134 7 Loo 9 & HN > & 133 2, H pee ( [Sn HoH Nowont 133 ” A, po TT < 135 ~ 7 & uN len SN a 136 ~ oH 135 TT 138 @ ~ = © HN 3p I rot 03 Py Ton mC 137 WN 448 Y=oH 139 WwW) 140 21 3 0 & HN. = oy CZ] 138 A > 0 H > HN, = ” Th N J 140 oH 141 N=0 4142 2 Se & HN. = as 2] 141 ~ zr slo OH JI \. 142 AN oH he 141 7 Pew ’ SR ( Na =N \» 143 Sk N+ 0 OH $ JOR Ne Sy \» 144 ANN TT 143 NO 144 2 Lhe Sew HN = OH & HN AJR Ame 145 146 A AN 145 C148 “ 3 Sy 0 y 0 > H = OH > 4 = A J "( Dy IE 147 es AN AY 2 ht 4H hoe =N v & 148 Z Ll, 147 - nd 148 9 Sy SAA yr “on & HN = G9 Te C! ud N ON cy 149 v A 150 2. SAO AY r OH % “7 149 oo 150 Cl rH = OH v W N< TO Dy N CX oi 151 & # A. 21 0 bad 151 = m2 @ <Q "HN. > OH " HN. Aon PROG ay & 153 Ns SA y HN oH 03 Do N & nH 155 “NEN 458 ; OH Dy 157 x’ iss 4 Loe & HN - Py - 157 A. Se | & HN 7 er Dg AY 159 =O 480 Lee N oH & HN A, 4 v JOR (Oy & 160 IY on Cw ar 4 Se - & nN _ on OR NS 158 C2, - Z z | Sr TX 4 un =) OH rr OH ™ Na, =) mq Det JOR (Org «© 161 «© 162 2 21. Rn L 2 oe oo 182 <1 Y ° Pa 7 XX) y — OH © HN SoA Xx 2 Sy 0 & HN. = J- ; 1684 7 Se 0 H & XEN . No =N . 166 L £ Cl Y oe] OH a = ~ JI - 168 L , 167 168 Le Ae " HN N* AIR 2 Shy \ OH ) & HN. 169 170 LSAT 168 Z le & HN. Foon 171 172 Lr \ PH 173 174 175 BN 176 x il “1 SN 0 & HN. = 175 ANG Sr Ct SRO 176 W a 177 N 178 Qe 1 & HN. OH CR Te N Skee & HN. TR > 177 N Re ~AAe § Y HN PS he ~ 179 180 179 180 z “1 Ae SI ARC ny x pl 181 182 hy Loe "HN = & HN sA i" 2 Loe & HN. = ! 184 183 . 184 7 Pew “3 4 YE Khe SOS SOR 185 / 186 185 . 188 Zz Lo SA & HN = ¥ HN. - SN SRC 187 188 ON AN 187 188 2 = SAA Lhe ” HN ” HN. JE J md 189 190 AY AN 189 190 ZZ 7 ~ HN. ” HN ome hm 191 192 AAI cd SP INO & H ( “ye v 404 S 193 ¥ 194 Z 2 Se 0 Se 0 & “OE “Jeet & "Or ov 2 “S ~ sy LI » , * Em et > SN il 3 196 ON - 195 196 7 | z SP $ Ee - HN & 2 OH HN on SOROS Imm Oe 197 LT 7 3 us ON 199 200 Sh Se 4 Xeon 200 pra @ Lhe "HN. J On 199 A 201 202 ea 7 | Ae ” HN. 201 AN 7 Lo H aN, = ODO 202 ON 203 204 & HN. CEO 203 AN Ske Si & HN, H Jon 204 2, ” oe A y 208 SN nl 205 Vv 208 Zz Se & HN. J ois 2] yy 0 "HN. OH = JO Oon i 208 AN 209 I 210 207 ' 208 4 SN 4 & “Co OO i = Nine OH = ~y N JE 209 I 210 A oo I Cm ~~ C] “Pe i - HN = JO I 210 ON Zz Loo & HN = - 1 ON ¥ HN. = OH TRH 212 213 214 211 212 Zz <M oe Zz 0” °N «J 0 Yodan hi = OH & A bi 0 0 =N 213 214 AN AN 7 > | 0 PO SSEP 214 A 7 | a 7 | A A BY = OH FHV And OH TRON JOR OR 215 216 AN BR Yon “1 Loe & HN. = 217 ON Ae IR ye AN YmoH °C CY ( Yeon nN 219 220 217 218 7 | 2 oS of Lo & HN — & HN. Iw Yoon oe So N Ao =N 219 220 Cl Sv 0 & nn H = Nin J 220 221 222 Cl A HN. TT 221 AN Clo ” Sr =, ned Ymon To % 222 ~N 223 224 Z Se 0 & H J 223 NN Z & un Ne OH ~, =N 224 ONS 225 228 2 Loe Yb omN 2 SL 225 AN Le & HN on AJR $5 Zn £48 226 N 0 ON & HN = } & HN. = OH JOR) "C J “C oS 227 228 A RN 229 230 7 Le & HN, = 229 ~~ ~ SA & HN = oH TE 3 230 231 232 ? y HN. oR 231 Loe & HN. IRN oF 233 234 £31 7 | SA & uN 2 one 233 . LES ORO W 234 OR 3 x 235 238 “1 N+ 0 & H 2 Ne J 235 AN 2 NL i 236 r T\,\OH \ “1 A HN. - 237 ON 7 Se 0 Ee > Ao SN > 238 AY 239 240 237 238 7 She Le & HN To oe OH HN, = ~ROL TIE 239 240 2 NR 7 Sp oO Ni =N 240 ON 241 242 Z Ad & nn 1 J Omkeon 242 ON cd | - Pe Xeon 24 Ls & uN JI Ombeon H 244 20 YX QL 0 "HN. = CE pee JG Omon 244 243 AN AN 7 ~ Pow LI & mn Todo JT Omeon Jomo 245 248 A ~~ x XE A Per = ~ £480 Ll h & HN = TT nAT 247 248 xe “7 YY Ie -— — Nor =N AQ 249 250 2 Sng® OH & nN, & J ~ 250 x" 249 “3 "HI > AJ 2 i AA ” HN. AT 252 251 252 2 "© HN, N*’ SI Jon & a Sh & HN & TT 264 253 254 Cl a a Le LE "Or Sou : HN, = N—{ OH Nor I & HN, 1 = On 256 255 258 7 Sh LI > 0 & HN TE JIE - Fo JE 257 268 Cl ¢ SN a] ” & “Oe No =n 258 2 "HI = I 257 258 @ = Ne 0 A "HN A = OH H — = ee Tier 250 B40 259 260 x Clo 7 TE SI XD, 0 0” °N ! & HN = JI 281 262 4 “7 & HN. = OH HN. = JIE Pat JE 298% 2R4 263 264 C1 Se Se "HN Se = IN— xX & HN Bee e: 1 ~ SA “hen 285 266 COE eT ~o ~~ i JIE 267 268 2) LI SA oS N° & HN. - "bon _ JI A Jo ll N 269 270 [} N & HN & HN SLE XTX 271 2712 Da RR S «0 Qa, Q 0 O07 N* ' & HN. = — es C1] N+ 0 < & uN 2 . > JOR NAS ~ 274 273 274 Zz = | Se Se - HN. - oH "HI = - I x JOR 275 276 LA N & uN = SB J oH ¥ H = ote 2717 28 Cl vr ” HN. Soo & HN. ATRIOS 280 279 280 - or & HN ? : H JR) C Con JRO 281 282 Y-oH 283 284 281 7 hy | J 283 LA N & Ye-C ~o N\A 284 XE 285 286 £33 LI SN 0 & HN - SR 285 Leo Yo LR 286 287 288 LI Bh 2 - 3 0 She 5 HN ¥ HN, GORE JIT on 287 208 " AN 7 ASA Ae Ho& " = DE RX 289 200 a ONS LA Lhe TORK OR The present invention provides a preparation method for the compound of formula I (including formula Ia-Ie) or the stereoisomer, the racemate, the tautomer, the isotopically labeled compound, the prodrug or the pharmaceutically acceptable salt thereof, but the preparation method is not limited to the method described below. In some embodiments, the preparation method may comprise: wii yr NN wg (Ra) NY RyLq pa Ral coon e 0 (2) HN \ M2 (Ra) Ny Rb Roh 0 Ry-W N -» Hy A - ©" hn 2~ H N TO « N sy Rp-w H RW N Mey M3 formula | reacting M-1 and M-2 to give M-3, wherein the reaction may be performed in the presence "1 M3 formula | (al) reacting M-1 and M-2 to give M-3, wherein the reaction may be performed in the presence of EDCILHCI and pyridine; and (a2) reacting M-3 and R«Li, wherein Ry is selected from R; and a group of R having hydroxyl with the hydroxyl substituted with © OO"; when Reis a group of Ri having hydroxyl with the P= Hoe, PO Ho hydroxyl substituted with =O” , the reaction requires to be performed in the presence of an acid and a reductant ro give the formula I, wherein the acid may be HCI, and the reductant may be sodium borohydride; Ri, R2, R3, m and W in the above steps are as defined in formula I, the L; is a leaving group and may be selected from halogen and -OTs. In some embodiments, the preparation method may comprise: i COOH 5 A (Racoon 3 NE N-Ry NR - / NR y N - — Rp-W N Rp-W N TT Rew "Cw Rp-W' N Na N2 N3 formula | reacting N-1 and RxL1, wherein Ry is selected from R; and a group of R; having hydroxyl wi the hydroxyl substituted with =~ © ; when Rx is a group of Rj having hydroxyl with the Po Ho O Hoo hydroxyl substituted with © 07 | the reaction requires to be performed in the presence of an acid and a reductant to give N-2, wherein the acid may be HCI, and the reductant may be sodium borohydride; (b2) reducing the N-2 obtained in the above step to give N-3, wherein a reductant may be Pd / C; and (b3) reacting the N-3 and M-2 to give the formula I, Ri, Ra, R3, m and W in the above steps are as defined in formula I, the L, is a leaving group and may be selected from halogen and -OTs, The present invention further provides a pharmaceutical composition comprising the compound of formula I or the stereoisomer, the racemate, the tautomer, the isotopically labeled compound, the prodrug or the pharmaceutically acceptable salt thereof disclosed herein, In some embodiments, the pharmaceutical composition disclosed herein further comprises a therapeutically effective amount of the compound of formula I or the stereoisomer, the racemate, the tautomer, the isotopically labeled compound, the prodrug or the pharmaceutically acceptable salt thereof disclosed herein, and a pharmaceutically acceptable carrier. The present invention further provides use of the compound of formula I or the stereoisomer, the racemate, the tautomer, the isotopically labeled compound, the prodrug or the pharmaceutically acceptable salt thereof in preparing IRAK inhibitor. The present invention further provides use of the compound of formula I or the stereoisomer, the racemate, the tautomer, the isotopically labeled compound, the prodrug or the pharmaceutically acceptable salt thereof in preparing a medicament for preventing and / or treating diseases or disorders mediated by IRAK. According to an embodiment of the present invention, the IRAK-mediated diseases or disorders are selected from tumors, gout, systemic lupus erythematosus, multiple sclerosis, metabolic syndrome, atherosclerosis, myocardial infarction, sepsis, inflammatory bowel disease, asthma, allergy, and the like. The present invention further provides use of the compound of formula I or the stereoisomer, the racemate, the tautomer, the isotopically labeled compound, the prodrug or the pharmaceutically acceptable salt thereof in preparing a medicament for preventing and / or treating diseases or disorders associated with interleukin-1 receptor-associated kinase. The present invention further provides a method for preventing and / or treating IRAK-mediated diseases or disorders, comprising administering to an individual in need thereof a therapeutically effective amount of the compound of formula I or the stereoisomer, the racemate, the tautomer, the isotopically labeled compound, the prodrug or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, In some embodiments, the IRAK is IRAK4-associated kinase. The present invention further provides a method for preventing and / or treating interleukin-1 receptor-associated diseases, comprising administering to an individual in need thereof a therapeutically effective amount of the compound of formula I or the stereoisomer, the racemate, the tautomer, the isotopically labeled compound, the prodrug or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition. According to an embodiment of the present invention, the diseases or disorders associated with interleukin-1 receptor-associated kinase are selected from tumors, gout, systemic lupus erythematosus, multiple sclerosis, metabolic syndrome, atherosclerosis, myocardial infarction, sepsis, inflammatory bowel disease, asthma, rheumatoid arthritis, septicemia, autoimmune disease, allergy, and the like. The method of the present invention may comprise administering the compounds disclosed herein alone or in combination with one or more other chemotherapeutic agents, Multiple drugs may be administered simultaneously or successively, Definitions and Abbreviations of Terms Unless otherwise stated, the definitions of groups and terms described in the specification and claims of the present application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions documented in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and incorporated with each other. The definitions of groups and the structures of the compounds in such combinations and incorporations should fall within the scope of the present specification, When a numerical range defined by "integer" is recited in the specification and claims of this application, it shall be construed as reciting both endpoints of the range and every integer within the range. For example, "an integer of 0 to 6" shall be construed to include every integer of 0, 1, 2, 3, 4, 5 and 6. The term "more" refers to three or more. The optionally substituted with a substituent described herein encompasses both unsubstituted and substituted with one or more substituents, for example, "optionally substituted with one, two or more R" means that it may be not substituted (unsubstituted) with one R or substituted with one, two or more R. The term "halogen" refers to F, Cl, Br and I. In other words, F, Cl, Br and I may be described as "halogen" in the specification. The term "aliphatic hydrocarbyl" includes saturated or unsaturated, and linear or branched or cyclic hydrocarbyl groups. The aliphatic hydrocarbyl may be selected from alkyl, alkenyl, alkynyl, and the like, has preferably 1-12 or 1-10 carbon atoms, and more preferably 1-6 carbon atoms, and specifically may include but is not limited to the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 1-ethylethenyl, 1-methyl-2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 1-hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, l-pentynyl, 1-hexynyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the "aliphatic hydrocarbyl" may optionally comprise one, two or more heteroatoms (which may be construed as optional insertion of heteroatoms into any C-C bond and C-H bond of the aliphatic hydrocarbyl). Suitable heteroatoms will be apparent to those skilled in the art and include, for example, sulfur, nitrogen, oxygen, phosphorus and silicon. The aliphatic hydrocarbyl comprising heteroatoms may be selected from the following groups: (Ci-Ce)aliphatic hydrocarbyloxy, (C1-Ce)aliphatic hydrocarbylthio, (Ci-Cs)aliphatic hydrocarbyloxy(Ci-Ce)aliphatic hydrocarbyl, (C1-Ce)aliphatic hydrocarbylthio(C1-Ce)aliphatic hydrocarbyl, N-(Ci-Cs)aliphatic hydrocarbylamino(C1-Ce)aliphatic hydrocarbyl, and N,N-di-(C1-Cs)aliphatic hydrocarbylamino(C1-Ce)aliphatic hydrocarbyl, for example, methoxy, ethoxy, propoxy, butoxy, pentoxy, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, propoxypropyl, N-methylaminomethyl, N-methylaminoethyl, N-ethylaminoethyl, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, and N,N-diethylaminoethyl; the "aliphatic hydrocarbyl" moieties contained in the other groups are defined as above. The term "Cs.12 cycloalkyl" refers to a saturated or unsaturated monovalent monocyclic or bicyclic hydrocarbon ring having 3-12 carbon atoms, and is preferably a "Cs.10 cycloalkyl". The term "Cs.10 cycloalkyl" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The Cs.i0 cycloalkyl may be a monocyclic hydrocarbyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or may be a bicyclic hydrocarbyl such as a decahydronaphthalene ring. The term "3-12 membered heterocyclyl" refers to a saturated or unsaturated monovalent monocyclic or bicyclic ring comprising 1-5 heteroatoms independently selected from N, O and S. The groups comprising heteroatoms are not aromatic, and the 3-12 membered heterocyclyl is preferably a "3-10 membered heterocyclyl", The term "3-10 membered heterocyclyl" refers to a saturated monovalent monocyclic or bicyclic ring comprising 1-5, preferably 1-3, heteroatoms selected from N, O and S. The heterocyclyl may be connected to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present). In particular, the heterocyclyl may include, but is not limited to: 4 membered rings such as azetidinyl or oxetanyl; 5 membered rings such as tetrahydrofuryl, tetrahydrothienyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl or pyrrolinyl; 6 membered rings such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or 7 membered rings such as diazepanyl. Optionally, the heterocyclyl may be benzo-fused. The heterocyclyl may be bicyclic, such as but not limited to a 5,5 membered ring such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6 membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazin-2(1 H)-yl ring. The ring containing nitrogen atoms may be partially unsaturated, i.e., it may comprise one or more double bonds, such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolinyl. According to the present invention, the 3-12 membered heterocyclyl may be further selected from the following groups: NH -%N | NH -N | NH SN NH IN INH AN NH SN JH AN TA NJ Ow + Jw Hw 4 Ww ACW Aw +O HOw Hw Hw TN TN CNL and The term "Ce.20 aryl" preferably refers to an aromatic or partially aromatic monocyclic, bicyclic or tricyclic monovalent hydrocarbon ring containing 6-20 carbon atoms, and is preferably "Ce.14 aryl". The term "Ce-14 aryl" preferably refers to an aromatic or partially aromatic monovalent monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms ("Ce-14 aryl"), in particular a ring having 6 carbon atoms ("Cs aryl"), such as phenyl; or a biphenyl, a ring having 9 carbon atoms ("Cs aryl") such as indanyl or indenyl, a ring having 10 carbon atoms ("Cio aryl") such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, a ring having 13 carbon atoms ("Ci3 aryl") such as fluorenyl, or a ring having 14 carbon atoms ("C14 aryl") such as anthracenyl. The term "5-14 membered heteroaryl" refers to an aromatic monovalent monocyclic, bicyclic or tricyclic ring which has 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5, 6, 9 or 10 carbon atoms, comprises 1-5, preferably 1-3 heteroatoms independently selected from N, O and S, and may be benzo-fused in each case. In particular, the heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, and isoindolyl; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like and benzo derivatives thereof, such as quinolyl, quinazolinyl, and isoquinolyl; or azocinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like. Unless otherwise specified, heterocyclyl or heteroaryl includes all possible isomeric forms thereof, e.g. positional isomers thereof. Accordingly, for some illustrative non-limiting examples, pyridinyl or pyridinylene includes pyridin-2-yl, pyridinylene-2-yl, pyridin-3-yl, pyridinylene-3-yl, pyridin-4-yl, and pyridinylene-4-yl; thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-yl, and thien-3-ylene. The "3-12 membered heterocyclyl" and "5-14 membered heteroaryl" disclosed herein may further comprise 5-12 membered heterocyclyl or 5-14 membered heteroaryl containing N, that is N-containing 5-12 membered heterocyclyl or 5-14 membered heteroaryl may be selected from corresponding groups defined by the "3-12 membered heterocyclyl" and "5-14 membered heteroaryl". According to the structure, the compounds disclosed herein may be chiral and may therefore exist in various enantiomeric forms. These compounds may therefore exist in racemic or optically active form. The compounds disclosed herein or intermediates thereof may be separated into enantiomers by chemical or physical methods well known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereoisomers are prepared from mixtures by reaction with optically active resolving agents. Examples of suitable resolving agents are optically active acids such as R- or S-tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable MN-protected amino acids (e.g, MN-benzoylproline or N-benzenesulfonylproline) or various optically active camphorsulfonic acids. Enantiomeric resolution by chromatography can be advantageously performed with the aid of optically active resolving agents, such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derivatized methacrylate polymers immobilized on silica gel. Suitable eluents for this purpose are mixtures of solvent containing water or alcohol, for example, lauric acid, salicylic acid, cinnamic acid, cyclopentanepropionic nicotinic pectinic acid, benzenesulfonic acid, p-toluenesulfonic acid, acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid, or thiocyanic acid. In addition, another suitable pharmaceutically acceptable salt of the compounds disclosed herein having sufficient acidity is an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., calcium salt or magnesium salt), an ammonium salt, or a salt formed with an organic base which provides a physiologically acceptable cation, for example a salt formed with: a sodium ion, a potassium ion, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trihydroxymethylaminomethane, aminopropanediol, or 1-amino-2,3,4-butanetriol. As an example, the pharmaceutically acceptable salts include salts formed by the group -COOH with the following: a sodium ion, a potassium ion, a calcium ion, a magnesium ion, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropanediol, or 1-amino-2,3,4-butanetriol. In addition, the basic nitrogen-containing groups may be quaternized with the following agents: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides such as benzyl and phenethyl bromides. As an example, pharmaceutically acceptable salts include hydrochloride, sulfate, nitrate, bisulfate, hydrobromide, acetate, oxalate, citrate, mesylate, formate, meglumine, and the like. Since the compounds disclosed herein may have a plurality of salt-forming sites, the "pharmaceutically acceptable salt" includes not only a salt formed at 1 salt-forming site of the compounds disclosed herein but also salts formed at 2, 3 or all of the salt-forming sites thereof. For this purpose, the molar ratio of the compound of formula I to a radical ion (anion) of an acid or a cation of a base required for salt formation may vary within a wide range, and may be, for example, 4:1 to 1:4, such as 3:1, 2:1, 1:1, 1:2, and 1:3. According to the present invention, the pharmaceutically acceptable anions include anions selected from those generated by the ionization of inorganic or organic acids, The "inorganic acid" includes, but is not limited to, hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, or nitric acid. The “organic acid" includes, but is not limited to, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, peroxosulfuric acid, 3-phenylpropionic acid, picric acid, pivalic 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic dodecylsulfuric ethanesulfonic acid, benzenesulfonic methanesulfonic acid, generated, when there are multiple asymmetric centers, a diastereoisomeric mixture is generated. In some cases, asymmetry may also exist due to hindered rotation about a particular bond, for example, the two substituted aromatic rings of a particular compound connected by the central bond may be asymmetric. Furthermore, the substituents may exist in cis- or trans-isomeric forms. The compounds disclosed herein also include all possible stereoisomers thereof, either in the form of a single stereoisomer or in the form of any mixture of the stereoisomers (e.g., R- or S-isomers, or E- or Z-isomers) in any proportion. Single stereoisomers (e.g., single enantiomers or single diastereoisomers) of the compounds disclosed herein may be separated by any suitable method in the prior art (e.g., chromatography, particularly, e.g., chiral chromatography). The term "tautomer" refers to functional isomers resulting from the rapid movement of an atom in a molecule between two positions. The compounds disclosed herein may exhibit the tautomerism. Tautomeric compounds may exist in two or more interconvertible forms. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in an equilibrium form. Trying to separate a single tautomer usually lead to a mixture, the physicochemical properties of which are consistent with the mixture of the compound. The position of the equilibrium depends on the chemical properties of the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; whereas in phenol, the enol form predominates. The present invention comprises all tautomeric forms of the compound, In the present invention, the compounds involved also include isotopically labeled compounds, which are identical to the compound of formula I, but have one or more atoms substituted with atoms with the atomic mass or mass number different from the atomic mass or mass number of those usually found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of H, C, N, O, 8, F and Cl, such as ?H, 3H, 13C, 1!C, C, I°N, "0, 170, 32p, 358, BF, and Cl. The compound or the prodrug thereof, or the pharmaceutically acceptable salts thereof comprising the above isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds disclosed herein, e.g., those into which radioactive isotopes such as *H and '*C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritium (i.e., *H) and carbon 14 (i.e., "C) isotopes are particularly preferred for their ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium (i.e., >H) may afford certain therapeutic advantages (e.g., increased in vivo half-life or reduced dose) resulting from greater metabolic stability and hence may be preferred in some circumstances. The compounds disclosed herein as claimed may be particularly limited to substitution with deuterium or tritium. Furthermore, the lack of separate specification of a hydrogen in a substituent as the term deuterium or tritium does not mean that the deuterium or tritium is excluded, on the contrary, the deuterium or tritium can also be included. The term “effective amount” or "therapeutically effective amount" refers to an amount of the compounds disclosed herein sufficient to effect the intended use, including but not limited to the treatment of a disease as defined below, The therapeutically effective amount may vary depending on the following factors: the intended use (in vitro or in vivo), or the subject and diseases or conditions being treated, such as weight and age of the subject, severity of the diseases or conditions and mode of administration, which can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on the following factors: the selected particular compound, the dosage regimen to be followed, whether to administer in combination with other compounds, the schedule of administration, the tissue to be administered and the physical delivery system carried. The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of types of excipients include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients are capable of enhancing the handling characteristics of the pharmaceutical formulation, i.e., making the formulation more amenable to direct compression by increasing flowability and / or adhesiveness. Examples of typical pharmaceutically acceptable carriers suitable for use in the above formulations include: saccharides, such as lactose, sucrose, mannitol, and sorbitol; starches, such as corn starch, tapioca starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose and methyl cellulose; calcium phosphates, such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearate, such as magnesium stearate and calcium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; nonionic, cationic and anionic surfactants; a glycol polymer; fatty alcohols; and grain hydrolysis solids and other nontoxic compatible excipients commonly available in pharmaceutical formulations, such as fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, and colorants. The term "solvate" refers to forms of the compounds disclosed herein in which a complex is formed by coordination of the compound in the solid or liquid state with solvent molecules. Hydrate is a particular form of the solvate in which the coordination occurs with water. In the present invention, the preferred solvate is a hydrate, Further, pharmaceutically acceptable solvates (hydrates) of the compound of formula I disclosed herein refer to co-crystals and clathrates formed of the compound of formula I and one or more molecules of water or other solvents in stoichiometric amounts. Available solvents for solvates include, but are not limited to water, methanol, ethanol, ethylene glycol and acetic acid. The term "prodrug", also known as "drug precursor", refers to a compound that is converted in vivo to the compound of the above general formula or of a particular compound. Such conversion is affected by hydrolysis of the prodrug in the blood or by enzymatic conversion of the prodrug into the parent structure in the blood or tissue. The prodrug disclosed herein may be esters, and in the present invention, the esters that may be used as prodrugs include phenyl esters, aliphatic (Ci.24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, compounds disclosed herein containing hydroxyl / carboxyl can be acylated to give a prodrug. Other prodrugs include phosphate esters, and those phosphate esters are obtained by phosphorylating via the hydroxyl on the parent structure. Reagent Names Corresponding to English Abbreviations of the Reagents English Abbreviations of Reagents Reagent Names m-CPBA m-chloroperoxybenzoic acid DCM Dichloromethane DIPEA N,N-diisopropylethylamine DMF N,N-dimethylformamide O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium HATU hexafluorophosphate EDCIHC1 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Py Pyridine DMAP 4-dimethylaminopyridine EA Ethyl acetate TsCl or TosCl p-Toluenesulfonyl chloride NMP N-methylpyrrolidin-2-one PE Petroleum ether DAST Diethylaminosulfur trifluoride Beneficial effects 1) The present invention provides a compound of general formula I with a novel structure, and experiments prove that the compound disclosed herein has a significant inhibition effect on IRAK4 activity, and has a good selective inhibition effect on IRAK4 activity relative to other kinases; 2) the compound disclosed herein has good medication safety, wide applicability and low toxicity, and the experiments prove that the compound of the present invention has a very low inhibition rate on human hERG, has no obvious time-dependent inhibition on human CYP3A4, has a moderate protein binding rate to plasma of human, rats and mice, and has little binding difference between species; at the same time, the compounds disclosed herein has no obvious inhibition effect on the 5 human CYP subtypes; 3) the compound disclosed herein has significant inhibitory effect on TNF-a release in LPS-induced Balb / c female mice; 4) the compound disclosed herein has good pharmacokinetic characteristics, shows excellent exposure and retention time in animals, and has suitable half-life and good drug absorption. DETAILED DESCRIPTION The technical scheme of the present invention will be further illustrated in detail with reference to the following specific examples. It should be understood that the following examples are merely exemplary illustration and explanation of the present invention, and should not be construed as limiting the protection scope of the present invention, All techniques implemented based on the aforementioned contents of the present invention are encompassed within the protection scope of the present invention. Unless otherwise specified, the starting materials and reagents used in the following examples are all commercially available products or can be prepared by known methods, Example 1: Synthesis of Compound 001 Reaction formula: THF 5 He MoM; TsO OH LOH 0 TsO 0 —MoMaBr ry 2 +Ts0 DS o x XJ — © THE 0 Ho—~ X 7 S22 . 150 — = ~ ~( 3 5 8 HNO3 FEINANRg NHpNH HO “28S Ne Pd / C JLre oA H,S0, OX DMF Ce pa 00 - — RTE N o F DMF o N T T H HN. TC o N ? H 8B 9 10 Ts0 = >, Hoe oo " Bo iN. ow 5 12 001 C] Sy 0 O HN pe o IIT Ren 001 C] SN 0 OH 13 1 1. Synthesis of compound 3 DMAP (42.5 g), compound 2 (63.4 g) and triethylamine (63.9 g) were added sequentially to a solution of compound 1 (50 g) in dichloromethane (500 mL} at 15 °C. The reaction system was stirred at 25 °C for 18 h. The reaction solution was added with dichloromethane (200 mL), and washed with water (300 mL x 2) and 1 M hydrochloric acid (300 mL x 3). The organic phase was dehydrated over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 3 (98 g, yield: 99%). 2. Synthesis of compound 4 1 M hydrochloric acid (300 mL) was added into a solution of compound 3 (50 g) in tetrahydrofuran (300 mL) at 15 °C. The reaction system was stirred at 25 °C for 20 h. At 0 °C, the reaction solution was adjusted to pH 9 with 1 M sodium hydroxide solution. Ethyl acetate (200 mL x 3) was added for extraction. The extracts were washed with saturated sodium chloride solution (300 mL), dehydrated over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was slurried with petroleum ether (150 mL) to give compound 4 (39 g, yield: 91%). 3. Synthesis of compounds 5&6 A solution of compound 4 (34.5 g) in tetrahydrofuran (200 mL) was dropwise added into a solution of methylmagnesium bromide (85.8 mL) in tetrahydrofuran (500 mL) at -40 °C. The reaction system was stirred at -40 °C for 4 h. After the reaction was quenched with saturated ammonium chloride solution (100 mL), ethyl acetate (500 mL x 3) was added for extraction, and the extracts were washed with saturated saline (300 mL), dehydrated over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound 5 (4.3 g, yield: 10% ), compound 6 (7.0 g, yield: 17% ) and the mixture (12 g). Compound 5 'H NMR (400 MHz, CDCls): 8 7.79 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 4.52-4.41 (m, 1H), 2.44 (s, 3H), 1.95-1.80 (m, 2H), 1.77-1.61 (m, 4H), 1.46-1.35 (m, 2H), 1.19 (s, 3H). Compound 6 'H NMR (400 MHz, CDCls): 8 7.79 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 4.74-4.64 (m, 1H), 2.44 (s, 3H), 1.92-1.79 (m, 2H), 1.77-1.62 (m, 4H), 1.49-1.38 (m, 2H), 1.23 (s, 3H). 4, Synthesis of compound 8 A solution of nitric acid (1.6 mL, 70%) in concentrated sulfuric acid (1.6 mL, 98%) was added dropwise to a solution of compound 7 (2.0 g) in concentrated sulfuric acid (12 mL, 98%) at -15 °C. The reaction system was stirred at -15 °C for 2 h after the completion of addition. The reaction solution was slowly poured into ice water, stirred for 5 min and filtered under vacuum. The filter cake was washed with water, and the solid was collected and dried under reduced pressure to give compound 8 (2.5 g, yield: 97%). 5. Synthesis of compound 9 Hydrazine hydrate (2.4 mL, 98%) was added into a solution of compound 8 (2.0 g) in DMF (20 mL). After the completion of addition, the reaction system was heated to 120 °C, stirred for 16 h, and cooled to room temperature. The reaction system was slowly poured into ice water, stirred, and filtered under vacuum, The filter cake was washed with water, and the solid was collected and dried under reduced pressure to give compound 9 (1.3 g, yield: 67%). 6. Synthesis of compound 10 Compound 9 (12.4 g) and palladium on carbon (7 g, 10%) were added sequentially to 400 mL of ethyl acetate at 15 °C. The reaction system was stirred for 18 h at 15 °C in hydrogen atmosphere after the completion of addition. After palladium on carbon in the reaction solution was filtered, the filtrate was dehydrated and concentrated to give compound 10 (10.4 g, yield: 99%). 7. Synthesis of compound 12 EDCLHCI (2.6 g) was added into a solution of compound 10 (1.5 g) and compound 11 (1.4 g) in Py (15 mL) at 25 °C. The reaction system was stirred at 25 °C for 16 h. The reaction solution was dehydrated and concentrated, and the residue was slurried with MeOH:H>O = 20 mL:20 mL to give compound 12 (1.3 g, yield: 48%). 8. Synthesis of Compound 001 2-((2-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-6-methoxy-2 H-indazol-5-yl)carbamoyl)-6-methyl pyridine 1-oxide Rou 9 SNF 0 & HN a - TIT ~o N — 001 001 Cesium carbonate (985 mg) was added into a solution of compound 12 (300 mg) and compound 5 (344 mg) in DMF (5 mL) at 25 °C. The reaction system was stirred at 90 °C for 16 h. The reaction solution was added into water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (CH3;CN:H2O (0.1% NH4HCOs3) = 15-45%, UV: 214 nm, flowrate: 15 mL / min) to give compound 001 (70 mg, yield: 17%). 'H NMR (400 MHz, DMSO-d6): § 14.16 (s, 1H), 8.78 (s, 1H), 8.34 (s, 1H), 8.32-8.30 (m, 1H), 7.77 (d, J="7.6 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.13 (s, 1H), 4.45 (s, 1H), 4.43-4.40 (m, 1H), 3.95 (s, 3H), 2.53 (s, 3H), 2.09-2.00 (m, 4H), 1.68-1.58 (m, 4H), 1.22 (s, 3H). LCMS: Rt = 3.646 min, [M+H]"=411.1. 9. Synthesis of compound 11 m-CPBA (25 g) was added into a solution of compound 13 (10 g) in DCM (200 mL) at 25 °C. The reaction system was stirred at 25 °C for 16 h. The reaction solution was filtered, and the filtrate was quenched with a saturated solution prepared from sodium sulfite (15.6 g). The reaction system was stirred for 2 h and extracted. The aqueous phase was adjusted to pH < 7 with hydrochloric acid and extracted with DCM (50 mL x 3). The organic phases were combined and concentrated, and the residue was slurried with EA (300 mL) to give compound 11 (10.1 g, yield: 90%). Example 2: Synthesis of Compound 010 Reaction formula: TosCl Hod XT) so XJ Toerso( mo-MMEBI rion MOM, ron( / x cL Ts0—~ XX D0) met KT Eero rota mon( enon TS 1 © 2 3 4 5 m-CPBA Z “ I m-CPBA | Ss ii Sp ns® " OH Oo OH 8 KNO3 ag dh io _ Jo Jo NH Pd / C “NHHcl ON = I 10 i NH AM ne N ON Xx F N H N F H Hy80, MN. ~ ON HN 3 LHC! = Bo li KNO3 XO» Ws Tw Pdic Cw | nm F Ne sy N I N N —_ H \ \ H Hz804 8 9 1 12 mo( yeH 4 7 heer \ Ty 0] SN eo} & HN. = — DG I 13 010 1. Synthesis of compound 2 DMAP (42.5 g), TsCl (63.4 g) and triethylamine (63.9 g) were added sequentially to a solution of compound 1 (50 g) in dichloromethane (500 mL} at 15 °C. The reaction system was stirred at 25 °C for 18 h. The reaction solution was added with dichloromethane (200 mL), and washed with water (300 mL x 2) and 1 M hydrochloric acid (300 mL x 3), The organic phase was dehydrated over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 2 (98 g, yield: 99%). 2. Synthesis of compound 3 1 M hydrochloric acid (300 mL) was added into a solution of compound 2 (50 g) in tetrahydrofuran (300 mL) at 15 °C. The reaction system was stirred at 25 °C for 20 h. At 0 °C, the reaction solution was adjusted to pH = 9 with 1 M sodium hydroxide solution. Ethyl acetate (200 mL x 3) was added for extraction. The extracts were washed with saturated sodium chloride solution (300 mL), dehydrated over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was slurried with petroleum ether (150 mL) to give compound 3 (39 g, yield: 91%). 3. Synthesis of compounds 4&5 A solution of compound 3 (34.5 g) in tetrahydrofuran (200 mL) was dropwise added into a solution of methylmagnesium bromide (85.8 mL) in tetrahydrofuran (500 mL) at -40 °C. The reaction system was stirred at -40 °C for 4 h. After the reaction was quenched with saturated ammonium chloride solution (100 mL}, ethyl acetate (500 mL x 3) was added for extraction, and the extracts were washed with saturated saline (300 mL), dehydrated over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound 4 (4.3 g, yield: 10% ), compound 5 (7.0 g, yield: 17% ) and the mixture (12 g). Compound 4 'H NMR (400 MHz, CDCls): 8 7.79 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 4.52-4.41 (m, 1H), 2.44 (s, 3H), 1.95-1.80 (m, 2H), 1.77-1.61 (m, 4H), 1.46-1.35 (m, 2H), 1.19 (s, 3H). Compound 5 "H NMR (400 MHz, CDCl3): 8 7.79 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 4.74-4.64 (m, 1H), 2.44 (s, 3H), 1.92-1.79 (m, 2H), 1.77-1.62 (m, 4H), 1.49-1.38 (m, 2H), 1.23 (s, 3H). 4. Synthesis of compound 7 m-CPBA (25 g) was added into a solution of compound 6 (10 g) in DCM (200 mL) at 25 °C. The reaction system was stirred at 25 °C for 16 h. The reaction solution was filtered, and the filtrate was quenched with a saturated solution prepared from sodium sulfite (15.6 g). The reaction system was stirred for 2 h and extracted. The aqueous phase was adjusted to pH < 7 with hydrochloric acid and extracted with DCM (50 mL x 3). The organic phases were combined and concentrated, and the residue was slurried with EA (300 mL} to give compound 7 (10.1 g, yield: 90%). 5. Synthesis of compound 9 80 mL concentrated sulfuric acid was added into a 500 mL three-necked bottle. The reaction system was cooled to -7 °C, slowly added with compound 8 (10 g) and stirred for 5 min at -7 °C, and then the reaction system was cooled to -15 °C, slowly added with potassium nitrate (8.9 g), and stirred at -15 °C for 1 h. The mixed reaction solution was poured into 1.2 L ice water. The precipitated solid was filtrated, and filter cake was dissolved in 2 L ethyl acetate. The reaction solution was added with 4 L sodium bicarbonate solution to adjust pH > 7, and extracted with ethyl acetate (2 L x 3). The organic phase was concentrated and dehydrated, and the residue was purified on a silica gel column (DCM:MeOH = 300:1) to give compound 9 (12.3 g, yield: 27%). 6. Synthesis of compound 11 Compound 9 (400 mg), compound 10 (1.81 g) and DIPEA (2.86 g) were added sequentially to 20 mL of DMF at room temperature. The reaction solution was stirred overnight at 80 °C in a closed container. After the reaction was completed, water was added, followed by three extractions with ethyl acetate. The extracts were concentrated under reduced pressure and purified on silica gel column (DCM:CH30H = 200:1) to give compound 11 (570 mg, yield: 83%). 7. Synthesis of compound 12 Compound 11 (80 mg), Pd / C (5 mg) were added sequentially to 10 mL of DMF at room temperature. The reaction solution was stirred overnight at 55 °C in hydrogen atmosphere. After the reaction was completed, the reaction solution was filtrated, and the filtrate was concentrated under reduced pressure and purified on a silica gel column (DCM:CH3;OH = 100:1) to give compound 12 mg, yield: 65%). yer OC] SN* Oo \ O° HN = 5 oN N - xrai-nrirdsd foto no arsTiitomrs oi re Cesium carbonate (936 mg) was added into a solution of compound 13 (300 mg) and compound 4 (409 mg) in DMF (6 mL) at 25 °C. The reaction system was stirred at 90 °C for 16 h. The reaction solution was added into water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (CH3CN:H0 (0.1% NHHCO3) = 20-70%, UV: 214 nm, flowrate: 15 mL / min) to give compound 010 (59 mg, yield: 14%). 'H NMR (400 MHz, DMSO-dc): 8 14.01 (s, 1H), 8.80 (s, 1H), 8.34 (s, 1H), 8.33-8.30 (m, 1H), 7.77-1.74 (m, 1H), 7.56 (1, J = 7.6 Hz, 1H), 7.33 (s, 1H), 4.44-4.41 (m, 2H), 2.72 (s, 6H), 2.52 (s, 3H), 2.06-2.01 (m, 4H), 1.68-1.55 (m, 4H), 1.23 (s, 3H). LCMS: Rt = 3.318 min, [M+H]* = 424.2. Example 3: Synthesis of Compound 013 Reaction formula: Pd / C NH,NH, HO OzN . OQ F HNO, TY TO NR NH HU TY YT, rel - sa ~ x J 1,80, oO F DMF oO N Le o F 1 oy So I H T ON HaN parC SI =O N N o H Q H 2 3 4 mo) 5 CX 6 8 ) Lo enc HCI NZ __ NaBH4 Towed SoH A A =o ° 013 Ll. Sy 0 ad wl 0" NSN 013 C] Sng > = "CIO N Ay I 9 1. Synthesis of compound 2 A solution of nitric acid (1.6 mL, 70%) in concentrated sulfuric acid (1.6 mL, 98%) was added dropwise to a solution of compound 1 (2.0 g) in concentrated sulfuric acid (12 mL, 98%) at -15 °C. The reaction system was stirred at -15 °C for 2 h after the completion of addition. The reaction solution was slowly poured into ice water, stirred for 5 min and filtered under vacuum. The filter cake was washed with water, and the solid was collected and dried under reduced pressure to give compound 2 (2.5 g, yield: 97%). 2. Synthesis of compound 3 Hydrazine hydrate 24 mL, 98%) was added into a solution of compound 2 (2.0 g) in DMF (20 mL). After the completion of addition, the reaction system was heated to 120 °C, stirred for 16 h, and cooled to room temperature. The reaction system was slowly poured into ice water, stirred, and filtered under vacuum, The filter cake was washed with water, and the solid was collected and dried under reduced pressure to give compound 3 (1.3 g, yield: 67%). 3. Synthesis of compound 4 Compound 3 (12.4 g) and palladium on carbon (7 g, 10%) were added sequentially to 400 mL of ethyl acetate at 15 °C. The reaction system was stirred for 18 h at 15 °C in hydrogen atmosphere after the completion of addition. After palladium on carbon in the reaction solution was filtered, the filtrate was dehydrated and concentrated to give compound 4 (10.4 g, yield: 99%). 4, Synthesis of compound 6 EDCLHCI (2.6 g) was added into a solution of compound 4 (1.5 g) and compound 5 (1.4 g) in Py (15 mL) at 25 °C. The reaction system was stirred at 25 °C for 16 h. The reaction solution was dehydrated and concentrated, and the residue was slurried with MeOH:H>O = 20 mL:20 mL to give compound 6 (1.3 g, yield: 48%). 5. Synthesis of compound 8 Cesium carbonate (3.3 g) was added into a solution of compound 6 (1 g) and compound 7 (1.3 g) in DMF (20 mL) at 25 °C. The reaction system was stirred at 90 °C for 16 h. The reaction solution was added into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was concentrated under reduced pressure, The residue was purified by preparative high performance liquid chromatography (CH;CN:H2O (0.1% NH4HCO;) = 20-60%, UV: 214 nm, flowrate: 15 ml / min) to give compound 8 (370 mg, yield: 25%). 6. Synthesis of compound 9 5 mL 2 M hydrochloric acid was added into a solution of compound 8 (350 mg) in dioxane (5 mL) at 25 °C. The reaction system was stirred at 25 °C for 16 h, The reaction solution was adjusted to pH > 7 with sodium carbonate solution and extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated under reduced pressure to give compound 9 (150 mg, yield: 48%). 7. Synthesis of Compound 013 2-((2-((1r,4r)-4-hydroxycyclohexyl)-6-methoxy-2 H-indazol-5-yl)carbamoyl)-6-methylpyridine 1-oxide 214 nm, Example 4: Synthesis of Compounds 016 and Compound 220 Reaction formula: O2N, ~~ AICI, Es NE ON HN - 0 N sg 2 iG N 1 H ti I H NN —= gO” ~~~ N= TT ou —— CT o H Ho” ~~} [I MeOHRT | ON ON N — N o H HO” ~~} LY 1 n ! 2 H 3 MeOH / RT 4 ~~ H 1 hn. 2 H 3 o ~ | wo x] Sie o 77 bmn i” 0 wo = TOR o N o [I] Ny NaBH, MeOH / RT Yeon LTR Jon 220 @ Cpe H Ny 1 220 C Sw 0 > O HN. a 2 0 NN J 016 1. Synthesis of compound 2 Compound 1 (2 g) and AICI; (4.13 g) were sequentially added into dichloromethane (150 mL) at 18 °C. The reaction system was stirred at 55 °C for 18 h, The reaction solution was quenched with water (50 mL), extracted with dichloromethane (150 mL} and then extracted with ethyl acetate (150 mL x 3). The organic phase was concentrated and dehydrated, and the residue was slurried with dichloromethane (30 mL) to give compound 2 (1.6 g, yield: 86%). 2. Synthesis of compound 3 Potassium carbonate (93 mg) was added into a solution of compound 2 (0.1 g) and iodoethane (105 mg) in DMF (2 mL) at 25 °C. The reaction system was stirred at 60 °C for 16 h. The reaction solution was added into water (20 mL), The reaction solution was extracted with ethyl acetate (5 mL x 3). The organic phase was concentrated under reduced pressure. The residue was purified on a silica gel column (petroleum ether:ethyl acetate = 2:1) to give compound 3 (0.1 g, yield: 86%). 3. Synthesis of compound 4 Pd / C (0.3 g) was added into a solution of compound 3 (1.1 g} in methanol (100 mL) at 25 °C. The reaction system was stirred at 25 °C for 16 h in hydrogen atmosphere at 760 Torr. The reaction solution was filtered, and the filtrate was concentrated by rotary evaporation to give compound 4 (0.71 g, yield: 76%). 4, Synthesis of compound 6 Compound 5 (558 mg) was added into a solution of compound 4 (710 mg) and EDCI (840 mg) in pyridine (25 mL) at 25 °C. The reaction system was stirred at 25 °C for 16 h. The reaction solution was added into water (100 mL). The reaction solution was extracted with ethyl acetate (30 mL x 3). The organic phase was concentrated under reduced pressure. The residue was purified on a silica gel column (dichloromethane:methanol = 60:1) to give compound 6 (0.67 g, yield: 54%). 5. Synthesis of compound 8 Compound 6 (630 mg) was added into a solution of compound 7 (945 mg) and Cesium carbonate (1.97 g) in DMF (25 mL) at 25 °C. The reaction system was stirred at 90 °C for 16 h. The reaction solution was added into water (100 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (CH;CN:H20 (0.1% NH4HCOs3) = 5-95%, UV: 214 nm, flowrate: 15 ml / min) to give compound 8 (160 mg, yield: 18%). 6. Synthesis of compound 9 The compound 8 (180 mg) was dissolved in a mixed solution of dioxane (30 mL) and 2 M hydrochloric acid (10 mL) at 25 °C. The reaction system was stirred at 45 °C for 16 h. The reaction solution was adjusted to pH > 7 with saturated sodium bicarbonate solution and extracted with ethyl acetate (30 mL x 3). The organic phase was concentrated by rotary evaporation to give compound 9 (180 mg, yield: 97%). 7. Synthesis of Compound 016 2-((6-ethoxy-2-((1r,4r)-4-hydroxycyclohexyl)-2 H-indazol-5-yl)carbamoyl)-6-methylpyridine 1-oxide and Compound 220 2-((6-ethoxy-2-((1s,45)4-hydroxycyclohexyl)-2 H-indazol-5-yl)carbamoyl)-6-methylpyridine 1-oxide po - CIE Joh 016 220 C SN oO ee N: BGS ~ I 220 2] O° HN Som 016 dride (50 mg) was added int Sodium borohydride (50 mg) was added into a solution of compound 9 (180 mg) in methanol (20 mL) at 0 °C. The reaction system was stirred at 25 °C for 1 h. The reaction solution was quenched with ammonium chloride solution (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (CH;CN:H20 (0.1% NH4HCO3)=20-50%, UV: 214 nm, flowrate: 15 mL / min) to give compound 016 (retention time Rt = 11.25 min, 123 mg, yield: 68%) and compound 220 (retention time Rt = 11.75 min, 30 mg, yield: 17%). Compound 016 'H NMR (400 MHz, CDCl): 8 14.30 (s, 1H), 8.88 (s, 1H), 8.45 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H), 7.43-7.36 (m, 2H), 7.03 (s, 1H),4.37-4.30 (m, 1H), 4.24 (q, J = 6.8 Hz, 2H), 3.82-3.80 (m, 1H), 2.63 (s, 3H), 2.28 (d, J = 12.8 Hz, 2H), 2.18 (d, / = 14.8 Hz, 2H), 2.06 (q, J = 13.2 Hz, 2H), 1.65-1.56 (m, 3H), 1.55-1.50 (m, 2H). LCMS: Rt= min, [M+H]* = Compound 220 'H NMR (400 MHz, CDCls): § 14.30 (s, 1H), 8.89 (s, 1H), 8.45 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H), 7.43-7.36 (m, 2H), 7.04 (s, 1H), 4.41-4.35 (m, 1H), 4.24 (q, J = 8.8 Hz, 2H), 4.14 (br s, 1H), 2.63 (s, 3H), 2.35 (q, J = 8.8 Hz, 2H), 2.08 (d, J = 8.4 Hz, 2H), 1.98 (d, J = 13.2 Hz, 2H), 1.75 (t, J = 13.2 Hz, 2H), 1.64 (t, J = 6.8 Hz, 3H). LCMS: Rt = 2.642 min, [M+H]* = 411.2, Example 5: Synthesis of Compound 025 Reaction formula: OTs x Br-Mg—<] A 2 . 3 a Y Tw 0 > C] Pe s 0 Cw LX, So JN o “Or (CO > To v 025 1. Synthesis of compound 3 A solution of compound 1 (3 g) in tetrahydrofuran (10 mL) was dropwise added into a solution of compound 2 (45 mL) in tetrahydrofuran (100 mL) at -40 °C. The reaction system was stirred at 0 °C for 8 h. After the reaction was quenched with saturated ammonium chloride solution (200 mL), ethyl acetate (200 mL x 3) was added for extraction, and the extracts were washed with saturated saline (400 mL), dehydrated over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound 3 (1.5 g, yield: 44%). 2 Synthesis of Compound 025 2-((2-((1r,4r)-4-cyclopropyl-4-hydroxycyclohexyl)-6-methoxy-2 H-indazol-5-yl)carbamoyl)-6-m ethylpyridine 1-oxide T\ LOH al 025 2 SN 0 jeeT8 Ni JC 025 Cesium carbonate (820 mg) was added into a solution of compound 4 (300 mg) and compound 3 (374 mg) in NMP (30 mL) at 25 °C. The reaction system was stirred at 90 °C for 16 h. The reaction solution was cooled and added with water (100 mL). Ethyl acetate was added for extraction (80 mL x 4). The organic phase was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (CH3CN:H0 (0.1% NH:HCO3) = 5-95%, UV: 214 nm, flowrate: 15 mL / min) to give compound 025 (79 mg, yield: 18%). 'H NMR (400 MHz, CDCLs): 14.13 (s, 1H), 8.89 (s, 1H), 8.45 (d, J = 12 Hz, 1H), 7.89 (s, 1H), 7.42-7.37 (m, 2H), 7.07 (s, 1H), 4.49-4.41(m, 1H), 4.05 (s, 3H), 2.64 (s, 3H), 2.38-2.22 (m, 4H),1.92-1.88 (m, 2H), 1.72-1.64 (m, 2H), 1.31-1.26 (m, 1H), 0.98 (s, 1H), 0.43-0.41 (m, 4H). LCMS: Rt =3.198, [M+H]* = 437.2. Example 6: Synthesis of Compound 163 Reaction formula: —on TsCl —on / —— a TI. ~ add Ho— \ — 10 2 Ts0— oo “Y= NHzNHz HzO HNO, T __ HNO; Je 0 'F ON ny > NHzNHz HO I — = NN DMF H re : o F oN —on ON. “ 2 © F 80, 0 F DMF 9 H o SN . 8 9 3 Pd / C 7 TT wW— NO 6 3G OH YY oO 6 HN —on Qe o N 1 5 163 “1. AINE Ny OH O° HN on ~o N 163 was concentrated pressure. The was purified performance liquid chromatography (CH3CN:H20 (0.1% NHsHCO3:) = 214 flowrate: 15 mL / min) to give con g, yield: 5. Synthesis of compound 5 Pd / C (400 mg) was added into a solution of compound 4 (1.3 g) in ethyl acetate (30 mL) at 30 °C and the reaction system was stirred for 16 h in hydrogen atmosphere. The organic phases were combined, and the reaction solution was filtered and concentrated under reduced pressure to give compound 5 (1.9 g, yield: 95%). 6. Synthesis of Compound 163 2-((2-(3-hydroxy-3-methylbutyl)-6-methoxy-2 H-indazol-5-yl)carbamoyl)-6-methylpyridine 1-oxide OH , ~ 2] SN o oO HN ~ ~ = 163 me) were added into a sc HATU (273 mg) and Et;N (145 mg) were added into a solution of compound 5 (120 mg) and compound 6 (81 mg) in DMF (2 mL) at 30 °C. The reaction system was stirred at 30 °C for 18 h. The reaction solution was concentrated under reduced pressure, and the crude product was further purified by preparative high performance liquid chromatography (CH3CN:H20 (0.1% NH4HCO3) = 5-95%, UV: 214 nm, flowrate: 15 mL / min} to give compound 163 (110 mg, yield: 60%). 'H NMR (400 MHz, DMSO-de): 5 14.13 (s, 1H), 8.78 (s, 1H), 8.31-8.28 (m, 2H), 7.77-7.75(m, 1H), 7.60-7.55(m, 1H), 7.09 (s, 1H), 4.50 (s, 1H), 4.44-4.40 (m, 2H), 3.93 (s, 3H), 2.53 (s, 3H), 2.04-2,00 (m, 2H), 1.15 (s, 6H). LCMS: Rt = 2,784 min, [M+H]" = 385.2. Example 7: Synthesis of Compound 284 Reaction formula: oo 3 TsCl TN _3 HO. TsO Oe 0 2 284 ZT] O° HN er 0-0 ay 284 1. Synthesis of compound 2 p-toluenesulfonyl chloride (2.3 g) was added into a solution of compound 1 (1 g), triethylamine (2.9 g) and DMAP (1.4 g) in DCM (20 mL) at 25 °C. The reaction system was stirred at 25 °C for 16 h. The reaction solution was washed with 1 N HC] (200 mL x 3). The organic phase was dried and concentrated to give compound 2 (2.1 g, yield: 75%). 2. Synthesis of Compound 284 2-((2-cyclopentyl-6-methoxy-2 H-indazol-5-yl)carbamoyl)-6-methylpyridine 1-oxide Cesium carbonate (1.6 g) was added into a solution of compound 3 (500 mg) and compound 2 (485 mg) in DMF (10 mL) at 25 °C. The reaction system was stirred at 90 °C for 16 h. The reaction solution was added into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (CH3CN:H>O (0.1% NHHCOs) = 25-60%, UV: 214 nm, flowrate: 15 mL / min) to give compound 284 (123 mg, yield: 20%). 'H NMR (400 MHz, DMSO-ds): 3 14.15 (s, 1H), 8.78 (s, 1H), 8.32-8.29 (m, 2H), 7.77-7.75 (m, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.13 (s, 1H), 4.97-4.90 (m, 1H), 3.96 (s, 3H), 2.53 (s, 3H), 2.22-2.13 (m, 2H), 2.10-2.01 (m, 2H), 1.92-1.82 (m, 2H), 1.74-1.65 (m, 2H). LCMS: Rt = 3.562 min, [M+H]"= 367.0. Example 8: Synthesis of Compound 285 Reaction formula: ry LI. N Se 0 O° HN. Np - Om 285 1. Synthesis of Compound 285 2-((2-cyclohexyl-6-methoxy-2H-indazol-5-yl)carbamoyl)-6-methylpyridine 1-oxide 7 Sy 0 ok als O° HN TT “ = 285 Cesium carbonate (1.3 g) was added into a solution of compound 2 (400 mg) and compound 1 (511 mg) in NMP (8 mL) at 25 °C. The reaction system was stirred at 90 °C for 16 h. The reaction solution was added into water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (CH3CN:H>O (0.1% NHHCOs) = 25-75%, UV: 214 nm, flowrate: 15 mL / min) to give compound 285 (68 mg, yield: 13%). 'H NMR (400 MHz, DMSO-ds): 8 14.15 (s, 1H), 8.79 (s, 1H), 8.32-8.29 (m, 2H), 7.78-7.76 (m, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.11 (s, 1H), 4.40-4.34 (m, 1H), 3.95 (s, 3H), 2.53 (s, 3H), 2.11-2.07 (m, 2H), 1.90-1.80 (m, 4H), 1.70 (d, J = 12.8 Hz, 1H), 1.50-1.40 (m, 2H), 1.31-1.23 (m, 1H). LCMS: Rt = 3.971 min, [M+H]"= 381.2. Example 9: Synthesis of Compound 286 Reaction formula: DAST -_ FE 3 oo be wn " F 3 — o "OO NF DAST - Ts0— x gr, Te0— o—— 2 286 NC) Sy 0 O° HN. - -l Co N SX 286 1. Synthesis of compound 2 DAST (6 g) was added into a solution of compound 1 (2 g) in DCM (70 mL) at 0 °C. The reaction system was stirred at 25 °C for 3 h. The reaction solution was added into water (50 mL). The reaction solution was extracted with dichloromethane (30 mL x 2). The organic phase was concentrated under reduced pressure. The residue was purified on a silica gel column (PE:EA = 10:1) to give compound 2 (1.8 g, yield: 82%). 2. Synthesis of Compound 286 2-((2-(4,4-difluorocyclohexyl)-6-methoxy-2 H-indazol-5-yl)carbamoyl)-6-methylpyridine 1-oxide “1 SN O Le iyi o ro F N— X ~o =N F 288 Cesium carbonate (1.6 g) was added into a solution of compound 3 (500 mg) and compound 2 (731 mg) in NMP (10 mL) at 25 °C. The reaction system was stirred at 90 °C for 16 h. The reaction solution was added into water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (CH3;CN:H2O (0.1% NH4HCOs) = 40-70%, UV: 214 nm, flowrate: 15 mL / min) to give compound 286 (129 mg, yield: 18%). 'H NMR (400 MHz, DMSO-dc): 8 14.17 (s, 1H), 8.80 (s, 1H), 8.35 (s, 1H), 8.32-8.29 (m, 1H), 7.78-7.76 (m, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.13 (s, 1H), 4.68-4.57 (m, 1H), 3.97 (s, 3H), 2.53 (s, 3H), 2.32-2.07 (m, 8H), LCMS: Rt = 3.692 min, [M+H]"= 417.2, Example 10: Synthesis of Compound 287 Reaction formula: wo=~ DS 2 CT SP & HN 2 XO | 287 1. Synthesis of Compound 287 2-((6-(dimethylamino)-2-((1s,4s)-4-hydroxy-4-methylcyclohexyl)-2 H-indazol-5-yl)carbamoyl)- 6-methylpyridine 1-oxide 2 SNe o Jah hor Oo HN — TIN | 287 Cesium carbonate (800 mg) was added into a solution of compound 1 (255 mg) and compound 2 (350 mg) in NMP (5 mL) at 25 °C. The reaction system was stirred at 90 °C for 16 h. The reaction solution was added into water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (CH;CN:H2O (0.1% NH4HCO3) = 35-60%, UV: 214 nm, flowrate: 15 mL / min) to give compound 287 (51 mg, yield: 15%). 'H NMR (400 MHz, CDCls): § 14.03 (s, 1H), 8.92 (s, 1H), 8.46 (d, J = 8.0 Hz, 1H), 7.89 (s, 1H), 7.41-7.35 (m, 3H), 4.37-4.31 (m, 1H), 2.84 (s, 6H), 2.63 (s, 3H), 2.37-2.27 (m, 2H), 2.11-2.05 (m, 2H), 1.93-1.85 (m, 2H), 1.61-1,58 (m, 2H), 1.33 (s, 3H). LCMS: Rt = 3.298 min, [M+H]* = 424.3, Example 11: Synthesis of Compounds 015 and Compound 288 Reaction formula: Ts0— Be ON > 0. yy 0. —~ X PdiC — X Ig oo) — ~g Ne) or) ON N © H 3 © J ~~, OH m-CPBA N ~r CL oO Oo Zz RB HN “I 2 Shoo Le m-CPBA Lo as > Yow md 5 ° DCM o 0° 2 — Cn X 7] w " p =N Oo O80 She ~ i Sm _ =o © NaBH, NaBH, “7 Sy o O HN = Tn i” " 8 7 ) “ SP SNP oO HN a oO HN ” sBH, Ge] (mon TIN Yon By ng N wig N 01s 288 8 015 288 1. Synthesis of compound 3 Compound 1 (5 g), compound 2 (26 g) and cesium carbonate (29 g) were sequentially added into DMEF (400 mL) at 20 °C, The reaction system was stirred at 90 °C for 24 h in nitrogen atmosphere. The reaction solution was cooled to 20 °C, added with water (800 mL) and extracted with ethyl acetate (800 mL x 3), The organic phase was washed with saturated sodium chloride solution (500 mL x 3), dehydrated over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) and slurried with MTBE (50 mL} to give compound 3 (1.2 g, yield: 14%). 2. Synthesis of compound 4 Pd / C (0.1 g) was added into a solution of compound 3 (1.1 g) in ethyl acetate (200 mL) at 25 °C and the reaction system was stirred for 16 h in hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure to give compound 4 (901 mg, yield: 90%). 3. Synthesis of compound 6 Compound 5 (900 mg) was dissolved in dichloromethane (20 mL), and the reaction solution was slowly added with mCPBA (2.5 g). The reaction system was stirred at 25 °C for 16 h. The reaction solution was filtered. The residue was quenched with aqueous sodium sulfite. The reaction solution was adjusted to pH < 7 with hydrochloric acid and extracted with dichloromethane (50 mL x 3). The organic phase was concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound 6 (0.68 g, yield: 69%). 4. Synthesis of compound 7 HATU (376 mg) and DIPEA (128 mg) were added into a solution of compound 6 (164 mg) and compound 4 (250 mg) in DMF (10 mL) at 25 °C. The reaction system was stirred for 16 h. The reaction solution was added with water (100 mL) and extracted with EA (20 mL x 3), The extracts were washed with saturated sodium chloride solution (200 mL), dehydrated over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel column chromatography (dichloromethane:methanol = 40:1) and slurried to give compound 7 (480 mg, yield: 99%). 5. Synthesis of compound 8 4 M hydrochloric acid (10 mL) was added into a solution of compound 7 (480 mg) in dioxane (10 mL) at 0 °C. The reaction system was stirred at 30 °C for 16 h, cooled to 0 °C, adjusted to pH = 8 with saturated NaHCO;3 solution, extracted with EA (40 mL x 5), washed with saturated NaCl (200 mL), dehydrated over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 8 (435 mg, yield: 99%). 7. Synthesis of Compound 015 2-((2-((1r,4r)-4-hydroxycyclohexyl)-6-methoxy-2 H-indazol-5-yl)carbamoyl)-6-isopropylpyridi ne 1-oxide and Compound 288 2-((2-((1s,4s)-4-hydroxycyclohexyl)-6-methoxy-2 H-indazol-5-yl)carbamoyl)-6-isopropylpyridi ne l-oxide 0158 288 “7 C] SyO SVEN o 0 o HN i Ne OH Tw gaat > I 01s 288 Sodium borohydride (118 mg) was added into a solution of compound 8 (435 mg) in methanol (20 mL) at 0 °C. The reaction system was stirred at 30 °C for 16 h. The reaction solution was adjusted to pH = 7 with saturated ammonium chloride, extracted with DCM (40 mL x 5) and washed with saturated NaCl (200 mL). The residue was purified by preparative high performance liquid chromatography (CH3CN:H20 (0.1% NHsHCOs} = 30-70%, UV: 214 nm, flowrate: 15 mL / min) to give compound 015 (Retention time Rt=28.13 min, 171 mg, yield: 39%) and compound 288 (Retention time Rt=29.25 min, 44 mg, yield: 10%). Compound 015 'H NMR (400 MHz, CDCls): 5 14.18 (s, 1H), 8.88 (s, 1H), 8.44(d, J = 5.2 Hz, 1H), 7.83 (s, 1H), 7.47-7.40 (m, 2H), 7.05 (s, 1H), 4.34-4.33 (m, 1H), 4.04 (s, 3H), 3.99-3.95 (m, 1H), 3.82-3.80 (m, 1H), 2.30-2.26 (m, 2H), 2.19-2.16 (m, 2H), 2.05 (q, J = 9.2 Hz, 2H), 1.60-1.50 (m, 2H), 1.36 (s, 3H).1.35 (s, 3H). LCMS: Rt =3.531, [M+H]" = 425.2. Compound 288 'H NMR (400 MHz, CDCl): § 14.17 (s, 1H), 8.88 (s, 1H), 8.44 (d, J = 5.2 Hz, 1H), 7.89 (s, 1H), 7.47-7.40 (m, 2H), 7.06 (s, 1H), 4.39-4.37 (m, 1H), 4.14 (s, 1H), 4.05 (s, 3H), 3.99-3.95 (m, 1H), 2.38-2.34 (m, 2H), 2.09-2.04 (m, 2H), 2.01-1.96 (m, 2H), 1.80-1.76 (m, 2H), 1.36 (s, 3H).1.35 (s, 3H). LCMS: Rt =3.472, [M+H]" = 425.2. Example 12: Synthesis of Compounds 014 and Compound 218 Reaction formula: OH *% 2 ( =X ( he... g 2 LIOH 2 m-CPBA ¥ oy ¥ OH o Oo o oO = 0 ( = 8 NN oN o 3 a 5 HCl r™ wv OH So © ri o-OX0 2 1 Sy 0 [a or fo. =X on a Zz Wi “J oO HN NaBH, O° HN. oo ‘ 0 HN. 8 014 218 1. Synthesis of compound 3 Pd(dppf)Cla (113 mg) and K3PO4 (13.4 g) were added into a solution of compound 1 (7.3 g) and compound 2 (6.5 g) in toluene (70 mL). The reaction system was stirred at 100 °C for 16 h in nitrogen atmosphere. The reaction solution was cooled and concentrated under reduced pressure. The residue was purified with thin-layer chromatography (petroleum ether:ethyl acetate = 20:1) to give compound 3 (1.2 g, yield: 20%). 2. Synthesis of compound 4 m-CPBA (5.7 g) was added into a solution of compound 3 (1.1 g) in DCM (100 mL) at 25 °C. The reaction system was stirred at 25 °C for 48 h, The reaction solution was quenched with a saturated solution prepared from sodium sulfite (2.4 g). The organic phase was washed with saturated sodium bicarbonate (100 mL x 3), dehydrated over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 4 (1.1 g, yield: 92%). 3. Synthesis of compound 5 Compound 4 (1.2 g) and LiOH.H20 (730 mg) were sequentially added into THF / H>O (30 mL / 10 mL) in nitrogen atmosphere. The reaction system was stirred at 30 °C for 4 h after the completion of addition. The reaction solution was added with water (50 mL). The aqueous phase was adjusted to pH = 7 with 1 N HCL. The reaction solution was extracted with ethyl acetate (100 mL x 3), washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered under vacuum, and concentrated under reduced pressure to give compound 5 (844 mg, yield 84%). 4. Synthesis of compound 7 DECI (427 mg) was added into a solution of compound 6 (450 mg) and compound 5 (319 mg) in pyridine (35 mL) at 25 °C. The reaction system was stirred for 16 h. The solvent was completely removed under reduced pressure. The reaction solution was added with water (100 mL) and extracted with DCM (100 mL x 3). The extracts were washed with saturated sodium chloride solution (200 mL), dehydrated over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was slurried with ethyl acetate (10 mL) to give compound 7 (314 mg, yield: 45%). 5. Synthesis of compound 8 4 M hydrochloric acid (250 mL) was added into a solution of compound 7 (289 mg) in tetrahydrofuran (25 mL) at 0 °C, The reaction system was stirred at 30 °C for 16 h, cooled to 0 °C, adjusted to pH = 8 with saturated NaHCO3 solution, and extracted with DCM (40 mL x 5), The extracts were washed with saturated NaCl (200 mL), dehydrated over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 8 (249 mg, yield: 95%). 6. Synthesis of Compound 014 2-cyclopropyl-6-((2-((1r,4r)-4-hydroxycyclohexyl)-6-methoxy-2 H-indazol-5-yl)carbamoyl)pyri dine 1-oxide and Compound 218 Synthesis of 2-cyclopropyl-6-((2-((1s,4s)-4-hydroxycyclohexyl)-6-methoxy-2 H-indazol-5-yl)carbamoyl)pyri dine 1-oxide 014 218 0 C] Sie 0 Sie 0 0 HN. O° HN _ Nit OH N J = JI 014 218 hvdride (67 me) was added into a solution of compound 8 (249 me) Sodium borohydride (67 mg) was added into a solution of compound 8 (249 mg) in methanol (20 mL) at 0 °C. The reaction system was stirred at 30 °C for 16 h. The reaction solution was adjusted to pH = 7 with saturated ammonium chloride, and extracted with DCM (40 mL x 5). The extracts were washed with saturated NaCl (200 mL). The residue was purified by preparative high performance liquid chromatography (CH3CN:H20 (0.1% NH4HCOs) = 30-70%, UV: 214 nm, flowrate: 15 mL / min) to give compound 014 (Retention time Rt=7.99min, 108 mg, yield: 43%) and compound 218 (Retention time Rt=8.50min, 14 mg, yield: 5%). Compound 014 'H NMR (400 MHz, CDCl3): 8 14.26 (s, 1H), 8.87 (s, 1H), 8.39 (d, J =8.0 Hz, 1H), 7.82 (s, 1H), 7.39-7.35 (m, 1H), 7.04 (s, 2H), 4.37-4.29 (m, 1H), 4.04 (s, 3H), 3.83-3.75 (m, 1H), 2.88-2.80 (m, 1H), 2.28-2.25 (m, 2H), 2.18-2.15 (m, 2H), 2.09-2.00 (m, 2H), 1.58-1.48 (m, 2H), 1.29-1.26 (m, 2H), 0.84-0.82 (m, 2H). LCMS: Rt=3.312, [M+H] =423.2. Compound 218 'H NMR (400 MHz, CDCls): § 14.20 (s, 1H), 8.88 (s, 1H), 8.40(d, J =8.0 Hz, 1H), 7.80 (s, 1H), 7.38-7.26 (m, 1H), 7.06 (s, 2H), 4.69 (s, 1H), 4.41-4.35 (m, 1H), 4.14 (s, 1H), 4.05 (s, 3H), 2.89-2.80 (m, 1H), 2.41-2.31 (m, 2H), 2.08-2.04 (m, 2H), 2.00-1.96 (m, 2H), 1.80-1.72 (m, 2H), 1.28-1.26 (m, 2H), 0.84-0.83 (m, 2H). LCMS: Rt=2.807, [M+H] =423.2. Example 13: Synthesis of Compound 187 Reaction formula: OH oTs ots oTs A A A oo oh Br—Mg—= HCI wo Co HCI ik 4 oe eS ee —~ 7% So So Ty Ho \ 2 3 5 HNO3 MINAS NHoNHo HO “27 NZ Pd / C ~ Cc 0 HNO3 ou So o E H,S04 o F Ce HNO3 Te NH NH, H,0 Nee PdiC C0 Ss SR, No — ! 0 E H,S0, DMF N N 0 12804 ° F o N @ H 8 8 9 x 11 10 C Sy 0 O° HN = OH E(x oS S$ 187 4 SN 0 - OH 19 12 1 1. Synthesis of compound 2 DMAP (42.5 g), TsCl (63.4 g) and triethylamine (63.9 g) were added sequentially to a solution of compound 1 (50 g) in dichloromethane (500 mL) at 15 °C. The reaction system was stirred at 25 °C for 18 h. The reaction solution was added with dichloromethane (200 mL), and washed with water (300 mL x 2) and 1 M hydrochloric acid (300 mL x 3). The organic phase was dehydrated over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 2 (98 g, yield: 99%). 2. Synthesis of compound 3 1 M hydrochloric acid (300 mL) was added into a solution of compound 2 (50 g) in tetrahydrofuran (300 mL) at 15 °C. The reaction system was stirred at 25 °C for 20 h. At 0 °C, the reaction solution was adjusted to pH = 9 with 1 M sodium hydroxide solution. Ethyl acetate (200 mL x 3) was added for extraction. The extracts were washed with saturated sodium chloride solution (300 mL), dehydrated over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was slurried with petroleum ether (150 mL) to give compound 3 (39 g, yield: 91%). 3. Synthesis of compound 5 Compound 3 (74.6 mL) was dropwise added into a solution of compound 4 (5.0 g) in tetrahydrofuran (100 mL) at -40 °C. The reaction system was stirred at -40 °C for 4 h. After the end of reaction, as detected by TLC, the reaction was quenched with saturated ammonium chloride solution (50 mL), ethyl acetate (100 mL x 3) was added for extraction, and the extracts were washed with saturated sodium chloride solution (50 mL), dehydrated over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound 5 (900 mg, yield: 16%). 4, Synthesis of compound 7 Concentrated sulfuric acid (80 mL) was added into a 1 L three-necked flask. The reaction system was stirred at -12 °C for 5 min (part of the concentrated sulfuric acid was in an icing state), then slowly added with compound 6 (10 g) at -12 °C, and reacted without great temperature fluctuation. The reaction solution was stirred at -12 °C for 5 min, then added dropwise slowly with a mixed solution of nitric acid (8 mL} and concentrated sulfuric acid (8 mL) at about -12 °C and stirred for 1.5 h at about -12 °C. The starting material was consumed completely as detected by a dot plate. The reaction solution was slowly poured into ice water, stirred at low temperature for 20 min, filtered and washed with water. The filtrate was evaporated to dryness under reduced pressure to give compound 7 (13 g, yield: 100%). 5. Synthesis of compound 8 Compound 7 (30 g) ‘was dissolved in DMF (450 mL), and slowly dropwise added with hydrazine hydrate (36.3 mL, 98%) at 0 °C. The reaction solution was stirred at 120 °C for 18 h. After the reaction was completed, the reaction solution was cooled, then slowly poured into ice water, stirred for 10 min, filtered and washed with water, The filtrate was evaporated to dryness under reduced pressure to give compound 8 (20 g, yield: 69%). 6. Synthesis of compound 9 Compound 8 (10 g) and palladium on carbon (5 g, 10%) were sequentially added into ethyl acetate (200 mL). The reaction solution was stirred at 20 °C for 16 h in hydrogen atmosphere. After the reaction was completed, celite was added to filter out the palladium on carbon, and the reaction solution was concentrated, and dried to give compound 9 (8 g, yield: 94%). 7. Synthesis of compound 11 m-CPBA (25 g) was added into a solution of compound 12 (10 g) in DCM (200 mL} at 25 °C. The reaction system was stirred at 25 °C for 16 h. The reaction solution was filtered, and the filtrate was quenched with a saturated solution prepared from sodium sulfite (15.6 g). The reaction system was stirred for 2 h and extracted. The aqueous phase was adjusted to pH < 7 with hydrochloric acid and extracted with DCM (50 mL x 3). The organic phases were combined and concentrated, and the residue was slurried with EA (300 mL} to give compound 11 (10.1 g, yield: 90%). 8. Synthesis of compound 10 EDCLHCI (2.6 g) was added into a solution of compound 9 (1.5 g) and compound 11 (1.4 g) in Py (15 mL) at 25 °C. The reaction system was stirred at 25 °C for 16 h. The reaction solution was dehydrated and concentrated, and the residue was slurried with MeOH:H>O = 20 mL:20 mL to give compound 10 (1.3 g, yield: 48%). 9. Synthesis of Compound 187 2-((2-((1r,4r)-4-ethynyl-4-hydroxycyclohexyl)-6-methoxy-2 H-indazol-5-yl)carbamoyl)-6-methy Ipyridine 1-oxide “ Loo ho HN OH ROIEWA I added into NMP (10 mL) at 30 °C. The reaction system was stirred at 90 °C for 18 h. After the reaction was completed, as detected by LCMS, the reaction solution was cooled to 30 °C, added with water (15 mL) to quench reaction, and extracted with ethyl acetate (10 mL x 3). The extracts were washed with saturated sodium chloride (10 mL), dehydrated over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (CH3CN:H2O (0.1% NH:HCO3) = 5-90%, UV: 214 nm, flowrate: 15 mL / min) to give compound 187 (85 mg, yield: 20%). 'H NMR (400 MHz, CDCls): 5 14.14 (s, 1H), 8.89 (s, 1H), 8.46 (dd, J 1= 7.6 Hz, J ;= 2.8 Hz, 1H), 7.87 (s, 1H), 7.45-7.37 (m, 2H), 7.07 (s, 1H), 4.44-4.33 (m, 1H), 4.06 (s, 3H), 2.69-2.60 (m, 4H), 2.33-2.27 (m, 4H), 2.25-2.17 (m, 2H), 1.90-1.79 (m, 2H). LCMS: Rt = 3.162 min, [M+H]" = 421.2 Example 14: Synthesis of Compounds 019 and Compound 292 Reaction formula: Hoy 2 J JN pac 0 A 5 HN . © N T H ON. nN TCO oO N T H ON HO’ N v v 3 70 x Yo 7 6 v a Vv 9 Lo Leo . "C-O% wo peal 7 veo, NaBH, > 019 292 o "CE Yoon o "0 v 019 v 292 1. Synthesis of compound 3 PPh; (15 g) was added into a solution of compound 1 (7 g) and compound 2 (3.37 g) in THF (200 mL) in ice bath. The reaction system was stirred for 10 min, DIAD (3.1 g) was slowly dropwise added into the reaction solution, and the reaction system was stirred at 30 °C for 18 h. The reaction solution was added with water (50 mL) and extracted with ethyl acetate (40 mL x 4). The organic phase was concentrated under reduced pressure. The residue was purified onsilica gel column chromatography (PE:EA = 10:1 to PE:EA = 2:1) to give compound 3 (6.0 g, yield: 66%). 2. Synthesis of compound 4 Pd / C (1.0 g, 10%) was added into a solution of compound 3 (6.5 g) in ethyl acetate (300 mL) at 15 °C and the reaction system was stirred at 30 °C for 18 h in hydrogen atmosphere at 760 Torr. The reaction solution was filtered and concentrated under reduced pressure to give compound 4 (4.5 g, yield: 80%). 3. Synthesis of compound 6 EDCLHCI 21g was added into a solution of compound 4 (1.5 g) and compound 5 (1.1 g) in pyridine (30 mL) at 25 °C. The reaction system was stirred at 25 °C for 16 h. The reaction solution was concentrated and evaporated, and the residue was purified on a silica gel column (PE:EA = 1:1) to give compound 6 (810 mg, yield: 32%). 4, Synthesis of compound 8 Cesium carbonate 23 g) was added into a solution of compound 6 (810 mg) and compound 7 (1.1 g) in DMF (15 mL) at 25 °C. The reaction system was stirred at 90 °C for 16 h. The reaction solution was added into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (CH3CN:H20 (0.1% NH4HCOs) = 30-55%, UV: 214 nm, flowrate: 15 mL / min) to give compound 8 (320 mg, yield: 28%). 5. Synthesis of compound 9 4mL2M hydrochloric acid was added into a solution of compound 8 (320 mg) in dioxane (4 mL) at 25 °C. The reaction system was stirred at 25 °C for 16 h, The reaction solution was adjusted to pH > 7 with sodium bicarbonate solution and extracted with ethyl acetate (10 mL x 2). The organic phase was concentrated under reduced pressure to give compound 9 (250 mg, yield: 86%). 6. Synthesis of Compound 019 2-((6-(cyclopropylmethoxy)-2-((17,4r)-4-hydroxycyclohexyl)-2 H-indazol-5-yl)carbamoyl)-6-me thylpyridine 1-oxide and Compound 292 2-((6-(cyclopropylmethoxy)-2-((1s,4s)-4-hydroxycyclohexyl)-2 H-indazol-5-yl)carbamoyl)-6-me thylpyridine 1-oxide oH MoH fol Sn 0 Oo "To 0 Le I vo Vv na v 018 v 202 - 1=UAIUC “7 Sye 0 O° HN = Tw oO N I 018 214 3.56-3.51 (m, 1H), 2.52 (s, 3H), 2.09-2.05 (m, 2H), 1.97-1.87 (m, 4H), 1.44-1.34 (m, 3H), 0.66-0.61 (m, 2H), 0.48-0.45 (m, 2H). LCMS: Rt = 3.391 min, [M+H]* = 437.2. Compound 292: 'H NMR (400 MHz, DMSO-d6): § 14.31 (s, 1H), 8.79 (s, 1H), 8.31-8.29 (m, 2H), 7.77-7.75 (m, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.08 (s, 1H), 4.49 (d, J = 6.8 Hz, 1H), 4.40-4.34 (m, 1H), 4.02 (d, J = 6.8 Hz, 2H), 3.87 (s, 1H), 2.52 (s, 3H), 2.33-2.22 (m, 2H), 1.56-1.75 (m, 4H), 1.66-1.60 (m, 2H), 1.41-1.34 (m, 1H), 0.65-0.61 (m, 2H), 0.49-0.45 (m, 2H), LCMS: Rt = 3.101 min, [M+H]* = 437.2. Example 15: Synthesis of Compound 291 Reaction formula: HCl ~0 No NaBH, N= 0 OE =e XO 2 3 TsCl NZ Sor 5 291 C] O HN a 5 29 1. Synthesis of compound 2 Compound 1 (800 mg) was dissolved in tetrahydrofuran (10 mL) at 0 °C. LiHMDS (1 M THF solution, 5.50 mL) was slowly dropwise added into the reaction solution at 0 °C, then the reaction solution was stirred for 60 min at 0 °C and slowly added with iodomethane (680 mg). The reaction system was reacted at 0 °C for 1.5 h. After the reaction was completed, the reaction solution was added with saturated ammonium chloride solution (10 mL} to quench reaction, then extracted with ethyl acetate (25 mL x 2), and concentrated under reduced pressure. The residue was purified on a silica gel column (petroleum ether:ethyl acetate = 7:1) to give compound 2 (420 mg, yield: 55%). 2. Synthesis of compound 3 Compound 2 (700 mg) and 3 M HCI (18 mL) were sequentially added into tetrahydrofuran (18 mL) at 0 °C. The reaction system was stirred at 50 °C for 5 h. After the reaction was completed, the reaction solution was added with aqueous sodium hydroxide solution (3 M) to adjust to pH = 8, then extracted with dichloromethane (20 mL x 2), and concentrated under reduced pressure. The residue was purified on a silica gel column (petroleum ether:ethyl acetate = 4:1) to give compound 3 (420 mg, yield: 78%). 3. Synthesis of compound 4 Compound 3 (390 mg) was dissolved in ethanol (8 mL) at 25 °C. The reaction solution was added dropwise with a solution of sodium borohydride (112 mg) in ethanol (1 mL) at -70 °C, and stirred at -70 °C for 1 h. After the reaction was completed, the reaction solution was added with water (8 mL) to quench reaction, and then extracted with ethyl acetate (15 mL x 2). The organic phase was concentrated under reduced pressure. The residue was purified on silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound 4 (280 mg, yield: 66%). 4, Synthesis of compound 5 Compound 4 (250 ‘mg), TosCl (406 mg), DMAP (261 mg) and triethylamine (0.5 mL) were sequentially added into dichloromethane (8 mL) at 28 °C. The reaction system was stirred at 28 °C for 18 h. After the reaction was completed, the reaction solution was concentrated and evaporated, and the residue was purified on silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to give compound 5 (370 mg, yield: 64%). 5. Synthesis of Compound 291 2-((2-((1r,4r)-4-cyano-4-methylcyclohexyl)-6-methoxy-2 H-indazol-5-yl)carbamoyl)-6-methylpy ridine 1-oxide (OX, 201 CT LY 0 & HN. = — Tw sprang... 291 Compound 5 (296 mg), compound 6 (350 mg), and cesium carbonate (808 mg) were sequentially added into DMF (6 mL) at 25 °C. The reaction system was stirred at 90 °C for 18 h after the completion of addition. After the reaction was completed, water (10 mL) was added to quench reaction, the reaction solution was extracted twice with ethyl acetate (40 mL). The organic phase was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (CH3CN:H.O (0.1% NHHCO;) = 5-95%, UV: 214 nm, flowrate: 15 mL / min) to give compound 291 (80 mg, yield: 19%). 'H NMR (400 MHz, CDCl): 8 14.14 (s, 1H), 8.88 (s, 1H), 8.45 (d, J = 7.6 Hz, 1H), 7.87 (s, 1H), 7.44-7.38 (m, 2H), 7.06 (s, 1H), 4.53-4.50 (m, 1H), 4.06 (s, 3H), 2.63 (s, 3H), 2.46-2.39 (m, 2H), 2.28-2.20 (m, 2H), 2.02-1.88 (m, 4H), 1.45 (s, 3H). LCMS: Rt =3.310 min, [M+H]" = 420.2 Example 16: Synthesis of Compound 002 Reaction formula: nom Wo, OC] Sy 0 0 OH — NaN —- HAN I ~ N 0 H 3 002 C7 Ry 0 NF O° HN A TC N o H 3 C3 a, of 0 NF o Xo > ~o Sy OH 002 1. Synthesis of compound 3 Compound 2 (1.0 g), compound 1 (0.91 g) and EDCI (1.6 g) were added into pyridine (15 mL) at 28 °C. The reaction system was stirred at 28 °C for 18 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was slurried with methanol and water to give the compound 3 (1.0 g, a yield: 56%). 2-cyclopropyl-6-((2-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-6-methoxy-2 H-indazol-5-yl)carba moyl)pyridine 1-oxide CR “7 Sy 0 & HN or Tn ~o N - Compound 3 (500 mg), compound 4 (675 mg) and cesium carbonate (1.26 g) were sequentially added into DMF (10 mL) at 25 °C. The reaction system was stirred at 90 °C for 18 h. After the reaction was completed, the reaction solution was cooled to 25 °C, added with water (5 mL) to quench reaction, and extracted with ethyl acetate (15 mL x 3). The extracts were washed with saturated brine (10 mL), dehydrated over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (CH3CN:H,0 = 20-45%, UV: 214 nm, flowrate: 15 mL / min) to give compound 002 (130 mg, yield: 19 %). 'H NMR (400 MHz, CDCls): 8 14.22 (s, 1H), 8.89 (s, 1H), 8.40 (dd, Ji = 2.0 Hz, J. = 8.0 Hz, 1H), 7.87 (s, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.14-7.01 (m, 2H), 4.46-4,34 (m, 1H), 4.05 (s, 3H), 2.91-2.81 (m, 1H), 2.30-2.08 (m, 4H), 1.93-1.82 (m, 2H), 1.76-1.69(m, 2H), 1.39 (s, 3H), 1.32-1.23 (m, 2H), 0.89-0.76 (m, 2H). LCMS: Rt = 2.859 min, [M+H] = 437.2 Example 17: Synthesis of Compound 289 Reaction formula: [>—NH, Oa AKL ALS Ht -CPBA Qa - 2 NSN cl NSNNpO om “ “ AL), AL) Hel NSN ON —_ NSN H H OH OH 3 O(N ~o N OH JAN C] Ye OO OH AL C] N Sy 5 ; Hoo hn TOs ~o sy OH 289 grt ON Ao NaN; ON ~o L, oN. A 7 ute A _ int mS i - 9 ” og EtOH go Na ACOH EtOH or EtOH No" “PSN. AcOH EtOH So Ng. HN _ s o N 1 mM 10 9 oe 1. Synthesis of compound 3 Compound 1 (5.0 g), compound 2 (2.3 g), cesium carbonate (13.4 g), Pdz(dba); (0.25 g) and BINAP (0.51 g) were sequentially added into methylbenzene (100 mL} at 26 °C. The reaction system was stirred at 80 °C for 18 h in nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to 26 °C, added with water (100 mL), and extracted with ethyl acetate (200 mL x 3). The extracts were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure. The residue was purified on silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 3 (1.3 g, yield: 30%). 2. Synthesis of compound 4 Potassium hydroxide (4.58 g} was added into a solution of compound 3 (1.3 g) in ethanol / water (40 mL / 10 mL). The reaction system was stirred at 90 °C for 16 h. The reaction solution was adjusted to pH = 6 with 1 M hydrochloric acid, and extracted with ethyl acetate (100 mL x 3). The extracts were washed with water (50 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 4 (1.12 g, yield: 77%). 3. Synthesis of compound 5 m-CPBA (1.86 g) was added into a solution of compound 4 (360 mg) in dichloromethane (50 mL) at 26 °C. The reaction system was stirred at 26 °C for 3 days. After the reaction was completed, the reaction solution was filtered, the filtrate was added with saturated sodium sulfite solution, adjusted to pH < 7 with hydrochloric acid, stirred at 26 °C for 2 h, and extracted with dichloromethane (200 mL x 3). The extracts were washed with saturated brine (100 mL), dehydrated over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel preparative thin layer chromatography (dichloromethane:methanol = 20:1) to give compound 5 (60 mg, yield: 15%). 4. Synthesis of Compound 289 2-(cyclopropylamino)-6-((2-((17,4r)-4-hydroxy-4-methylcyclohexyl)-6-methoxy-2 H-indazol-5-y I)carbamoyl)pyridine 1-oxide OR : "OH 289 AL] YY O° HN = - gw < ~o N —- 289 Compound 5 (49 mg), compound 6 (69 mg), HATU (118 mg), and DIPEA (66 mg) were added into DMF (5 mL). The reaction system was stirred at 25 °C for 18 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (CH3CN:H.O = 30-95%, UV: 214 nm, flowrate: 15 mL / min) to give compound 289 (95 mg, yield: 83%). '"H NMR (400 MHz, CDCl3): 3 14.29 (s, 1H), 8.89 (s, 1H), 7.86 (1, J = 6.4 Hz, 2H), 7.41 (t, J = 8.0 Hz, 1H), 7.15(s, 2H), 7.07 (s, 1H), 4.43-4.38 (m, 1H), 4.04 (s, 3H), 2.61 (br s, 1H), 2.25-2.13 (m, 4H), 1.89-1.85 (m, 1H), 1.75-1.64 (m, 4H), 1.39 (s, 3H), 0.93-0.90 (m, 2H), 0.74-0.72 (m, 2H). LCMS: Rt = 3.308 min, [M+H]" = 452.2. 5. Synthesis of compound 9 NaN; (13.2 g) was added into a solution of compound 10 (34 g) in ethanol (350 mL) at 0 °C. The reaction system was stirred at 25 °C for 16 h, which was directly used in the next step after the 96%). Example 18. Synthesis of Compound 175 Reaction formula: xz Ko 9 Lo & wm = OH 175 1. Synthesis of Compound 175 2-((2-((1r,4r)-4-(cyanomethyl)-4-hydroxycyclohexyl)-6-methoxy-2 H-indazol-5-yl)carbamoyl)-6 -methylpyridine 1-oxide OC] O° HN. _ OH ST Orn 175 vA Trtnia eri An AR RAR raiind 3 Cesium carbonate (1.4 g) was added into a solution of compound 1 (520 mg) and compound 2 (806 mg) in DMF (10 mL) at 25 °C. The reaction system was stirred at 90 °C for 16 h. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (CH3CN:H20 (0.1% NHsHCOs) = 20-40%, UV: 214 nm, flowrate: 15 mL / min) to give compound 175 (64 mg, yield: 8%). 'H NMR (400 MHz, DMSO-ds): 8 14.16 (s, 1H), 8.79 (s, 1H), 8.37 (s, 1H), 8.32-8.29 (m, 1H), 7.78-1.76 (m, 1H),7.58 (t, J = 8.0 Hz, 1H), 7.11 (s, 1H), 5.20 (s, 1H), 4.49-4.45 (m, 1H), 3.95 (s, 3H), 2.82 (s, 2H), 2.53 (s, 3H), 2.14-2.01 (m, 4H), 1.84-1.80 (m, 2H), 1.71-1.64 (m, 2H). LCMS: Rt = 9.367 min, [M+H]" = 436.2 Example 19: Synthesis of Compound 176 Reaction formula: OTs g J 2 Q SN 0 O° HN. Toy N N © H CY Sy 0 om = OH Ne l ZN Soe Of 1. Synthesis of Compound 176 2-((2-((1r,4r)-4-(cyanomethyl)-4-hydroxycyclohexyl)-6-methoxy-2 H-indazol-5-yl)carbamoyl)-6 -cyclopropylpyridine 1-oxide C] Sy o Ni Dz ZN Se Oe 176 ald QO AROT wat and raatiim car ARA Compound 8 (420 mg), compound 9 (601 mg) and cesium carbonate (1.06 g) were sequentially added into DMF (10 mL} at 25 °C. The reaction system was stirred at 90 °C for 16 h. After the reaction was completed, the reaction solution was cooled to 25 °C, added with water (5 mL) to quench reaction, and extracted with ethyl acetate (10 mL x 3). The extracts were washed with saturated brine (10 mL), dehydrated over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (CH3CN:H,0 = 25-55%, UV: 214 nm, flowrate: 15 mL / min} and by silica gel preparative thin layer chromatography (dichloromethane:methanol = 20:1) to give compound 176 (25 mg, yield: 4 %). 'H NMR (400 MHz, CDCl): 8 14.25 (s, 1H), 8.89 (s, 1H), 8.39 (dd, Ji = 2.0 Hz, J> = 8.0 Hz, 1H), 7.86 (s, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.09-7.03 (m, 2H), 4.53-4.43 (m, 1H), 4.05 (s, 3H), 2.90-2.81 (m, 1H), 2.76 (s, 2H), 2.33-2.17 (m, 4H), 2.13-2.03 (m, 2H), 1.99-1.93(m, 1H), 1.89-1.73 (m, 2H), 1.30-1.26 (m, 2H), 0.88-0.80 (m, 2H). LCMS: Rt = 3.553 min, [M+H]'= 462.2 Example 20: Synthesis of Compound 042 Reaction formula: TE Or 4 oS I & on 2 042 HN i 7 2, a 2 oF Or Lhe 9 Sy gO - - 0 Sup? — ® "Oe Oo OH Oo OH o SN 2 042 2. Synthesis 2-((2-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-6-methoxy-2 H-indazol-5-yl)carbamoyl)-6-metho xypyridine 1-oxide 2] o Sy” 0 0° HN. - s en oO N T 042 AA ZT wired ITATTT 72311 mar} Compound 2 (92 mg), compound 4 (150 mg), HATU (311 mg) and triethylamine (165 mg) were added into DMF (5 mL) at 25 °C. The reaction system was stirred at 25 °C for 16 h. After the reaction was completed, the reaction solution was added with water (5 mL) to quench reaction, and extracted with ethyl acetate (5 mL x 3). The extracts were washed with saturated brine (10 mL), dehydrated over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (CH3CN:H20 = 10-40%, UV: 214 nm, flowrate: 15 mL / min) to give compound 042 (96 mg, yield: 41 %). 'H NMR (400 MHz, CDCl3): 8 14.15 (s, 1H), 8.89 (s, 1H), 8.22 (dd, Ji = 2.0 Hz, J» = 8.0 Hz, 1H), 7.86 (s, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.11-7.02 (m, 2H), 4.44-4.34 (m, 1H), 4.16 (s, 3H), 4.03 (s, 3H), 2.29-2.08 (m, 4H), 1,91-1,82 (m, 2H), 1.73-1.69 (m, 2H), 1.39 (s, 3H). LCMS: Rt = 2.713 min, [M+H]" = 427.2 Example 21: Synthesis of Compound B N-(2-((17,4r)-4-hydroxy-4-methylcyclohexyl)-6-methoxy-2 H-indazol-5-yl)-6-methylpicolinamide via TTT x l Na OH 2 o mn Sp HN. a aad RARaEEETL er JAS AREER A Z Le HN. a OH B TU (249 me). and DIPEA ( Compound 1 (150 mg), compound 2 (75 mg), HATU (249 mg), and DIPEA (141 mg) were sequentially added into DMF (5 mL} at 25 °C, The reaction system was stirred at 25 °C for 16 h. The reaction solution was added with water (50 mL}, and extracted with ethyl acetate (10 mL x 3). The extracts were washed with saturated brine (10 mL), dehydrated over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (CH;CN:H20 = 30-95%, UV: 214 nm, flowrate: 15 mL / min) to give a white solid (170 mg, yield: 79%). 1H NMR (400 MHz, CDCI3): 5 10.82 (s, 1H), 8.85 (s, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.87 (s, 1H), 7.78 (t, J =7.6 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 7.08 (s, 1H), 4.43-4.37 (m, 1H), 4.03(s, 3H), 2.66 (s, 3H), 2.27-2.13 (m, 4H), 1.89 (br s, 1H), 1.76-1.68 (m, 4H), 1.40 (s, 3H). LCMS: Rt = 3.604 min, [M+H]+ = 395.2. Biological Evaluation The following test examples are used for further explaining the present invention, but are not intended to limit the scope of the present invention. The structure of compound A in biological test examples: The structure of compound B synthesized in Example 21 in biological test examples: 4 SN Oo HN Tne pat ~o =N B. Test Example 1. Determination of inhibition of human IRAK4 by the compounds disclosed herein Major materials ATP (Sigma, CAT No. A7699-1G) DMSO (Sigma, CAT No. D2650) EDTA (Sigma, CAT No. E5134) HEPES (Sigma, CAT No. V900477-500G) DTT (Sigma, CAT No. D0632-25g) Brij-35 (Sigma, CAT No. B4184) 96-well plate (Corning, CAT No. 3365) 384-well plate (Corning, CAT No, 3573) Procedures The inhibitory activity of the compounds on IRAK4 at the Km concentration of ATP was measured in IRAK4 MSA (Mobility-Shift Assay, a mobility detection of microfluidic chip technology) as described below. A recombinant fusion protein of N-terminal GST (glutathione-S-transferase) and human IRAK4 was used as enzyme (GST-IRAK4, kinase IRAK4 (Carna, CAT No. 09-145)) at a final concentration of 1 nM; ATP (Sigma, CAT No. A7699-1G) was at a final concentration of 37 pM; the substrates used for the kinase reaction were 5-FAM (5-carboxyfluorescein)-labeled polypeptide (5-FAM-IPTSPITTTYFFFKKK-COOH) and substrate peptide FAM-P8 (GL Biochem, CAT No. 112396) at final concentrations of 5 uM. In this assay, 500 pM stock solutions of the compounds were prepared in 100% DMSO, and serially 4-fold diluted to the 10th concentration gradient with 100% DMSO, followed by a 10-fold dilution in the compound buffer (50 mM HEPES, pH 7.5, 0.00015% Brij-35) to give intermediate dilutions of the compounds at a final concentration of 10 uM-0.04 nM containing 10% DMSO. 5 pL of the intermediate dilution was transferred into a black 384-well plate, IRAK4 was diluted to 2.5 nM in the kinase buffer (50 mM HEPES, pH 7.5, 0.00015% Brij-35, 2 mM DTT). 10 pL of the IRAK4 dilution was transferred to the 384-well plate and co-incubated with the compound for 10-15 min. The substrate and ATP were diluted to 12.5 uM and 92.5 uM with reaction buffer (50 mM HEPES, pH 7.5, 0.00015% Brij-35, 10 mM MgCl), respectively. 10 pL of the dilution was transferred to a 384-well plate and incubated at 28 °C for 1 h. The reaction was terminated by adding 25 pL of 50 mM EDTA to the 384-well plate. The inhibition rate of IRAK4 by the compounds was calculated by measuring the rate of phosphorylated substrate using a Caliper EZ Reader (PerkinElmer) and the ICso was calculated by XL-fit software. Results show that the compounds disclosed herein have significant inhibition effect on IRAK4 activity, and the ICso (nM) is less than 100, preferably less than 30. In particular, some exemplary compound activity values are as follows: ICso values for the compounds disclosed herein inhibiting human IRAK4 activity are shown in Table 1. Table 1. ICso for inhibiting human IRAK4 activity Compound ID ICs0 (nM) Compound B 30.0 001 6.0 002 37 010 11.0 013 7.6 014 25 015 54 016 £1 019 8.1 025 13.0 163 23.0 175 71 176 43 187 92 218 83 220 14.0 284 28.0 285 59 286 14.0 287 13.0 288 13.0 289 1.7 201 14.0 202 14 Test Example 2. Determination of inhibition of human IRAK1 by the compounds disclosed herein This assay evaluated the inhibitory effect of the compounds on human IRAK1 activity with the same materials as in Test Example 1. The inhibitory activity of the compounds on IRAK1 at the Km concentration of ATP was measured in IRAK1 MSA (Mobility-Shift Assay, a mobility detection of microfluidic chip technology) as described below. A recombinant fusion protein of N-terminal GST (glutathione-S-transferase) and human IRAKI was used as enzyme (GST-IRAKI, kinase IRAK1, Carna) at a final concentration of 3 nM; ATP (Sigma) was at a final concentration of 97 uM; the substrates used for the kinase reaction were 5-FAM (5-carboxyfluorescein)-labeled polypeptide (5-FAM-IPTSPITTTYFFFKKK-COOH) and substrate peptide FAM-P8 (GL Biochem) at final concentrations of 5 uM. In this assay, 500 uM stock solutions of the compounds were prepared in 100% DMSO, and serially 4-fold diluted to the 10th concentration gradient with 100% DMSO, followed by a 10-fold dilution in the compound buffer (50 mM HEPES, pH 7.5, 0.00015% Brij-35) to give intermediate dilutions of the compounds at a final concentration of 10 uM-0.04 nM containing 10% DMSO. 5 uL of the intermediate dilution was transferred into a black 384-well plate. IRAKI was diluted to 7.5 nM in the kinase buffer (50 mM HEPES, pH 7.5, 0.00015% Brij-35, 2 mM DTT). 10 pL of the IRAK| dilution was transferred to the 384-well plate and co-incubated with the compound for 10-15 min. The substrate and ATP were diluted to 12.5 pM and 242.5 pM with reaction buffer (50 mM HEPES, pH 7.5, 0.00015% Brij-35, 10 mM MgCl), respectively. 10 uL of the dilution was transferred to a 384-well plate and incubated at 28 °C for 1 h, The reaction was terminated by adding 25 pL of 50 mM EDTA to the 384-well plate. The inhibition of IRAK1 by the compounds was calculated by measuring the rate of phosphorylated substrate using a Caliper EZ Reader (PerkinElmer) and the ICso was calculated by XL-fit software. Results show that the compounds disclosed herein have significant selective inhibitory activity on IRAK4, and the ICso (nM) ratio of IRAK1 to IRAK4 is more than 500, preferably more than 200. In particular, some exemplary compound activity values are shown below: ICso values for the compounds disclosed herein inhibiting human IRAK activity are shown in Table 2. Table 2. ICso for inhibiting human IRAK 1 activity Compound ID | IRAKI1 ICso (nM) IRAKI1 ICso (nM) / IRAK4 ICs0 (nM) 163 2993 130.1 001 4039 673.2 As can be seen from Table 2, the compounds disclosed herein have significant selectivity for human IRAK4 compared to IRAKI. Test Example 3. Experiments for determining hERG of the compounds disclosed herein This experiment evaluated the cardiac safety of the compounds disclosed herein, and an HEK-293 cell line stably expressing hERG potassium ion channel was used for detection. Instruments: Amplifier: purchased from HEKA (Germany), EPC10 Micromanipulator: purchased from Sutter Instruments (USA), MP225 Micropipette puller: purchased from Sutter Instruments (USA), P97 Microscope: purchased from Nikon, TE300 Capillary glass tubing: purchased from Sutter Instruments (USA), BF150-86-10 Data acquisition and analysis software: PatchMaster, Igor Pro 6.0 and GraphPad Prism 5.0 Procedures: Test compound stocks were diluted in DMSO into 0.3 mM, 1 mM, and 3 mM dilutions. Test compound stocks were diluted in an extracellular buffer (140 mM NaCl, 3.5 mM KCI, 1 mM MgCl, 2 mM CaClz, 10 mM glucose, 10 mM HEPES, 1.25 mM NaH,POs, adjusted to pH 7.4 with NaOH) to give working solutions of the test compounds at concentrations of 0.3 uM, 1 uM, 3 uM, 10 uM and 30 uM. The working solutions of the test compounds were ultrasonically treated for 20 min. Patch clamping: Under an inverted microscope, recording electrodes were controlled by micromanipulator to contact with the cell. A negative voltage was applied to create a G-omega shaped connection, After forming the G-omega shaped connection, a rapid capacitance compensation was given. Under the continuous negative voltage, the cell membrane was ruptured to form a whole-cell recording configuration. In the whole-cell recording configuration, slow capacitance compensation was given, and the values of membrane capacitance and series resistance were recorded. Voltage stimulation scheme for cellular hRERG potassium current: The cell membrane clamping voltage was -80 mV; the voltage was first elevated from -80 mV to +30 mV, held for 2.5 sec, and rapidly raised to and held at -50 mV for 4 sec, thus exciting the hERG channel tail current. Data acquisition was performed every 10 sec. -50 mV was used for drain current detection. The cover glasses planted with cells were placed in the recording chamber of an inverted microscope. Negative control and test compounds flowed through the recording chamber in an ascending order of concentration by gravity perfusion to quickly act on the cells, During the recording, the extracellular buffer was continuously circulated by a vacuum pump. The current detected in a cell in the negative control was used as the background for the cell. Each concentration was allowed to act for 5 min or until the current was stabilized, All experiments were performed at room temperature, Data analysis: . : Peak tail current compound. The current of each concentration was normalized first (—————— EOUT7) and then the Peak tail current vehicle Popes Peak tail current compound. : Yond inhibition rate was calculated (1 — ZE2X Ia CUITTENE COMPOURA,, Ric statistics were calculated for Peak tail current vehicle each concentration, including mean, standard deviation (SD), standard error (SE), and replicates (n). The dose-dependent curve was fitted with the following equation and the half maximal inhibitory concentration (ICso) of the test compounds was calculated: Wherein C represents the test compound concentration, ICso represents the half maximal inhibitory concentration, and h represents the Hill coefficient. Curve fitting and calculation of ICso were done by GraphPad Prism 5.0 software. Results show low inhibition rates of the compounds disclosed herein for human hERG, which are even significantly superior to the control compound A. The inhibition rate of the compounds at 30 uM for hERG is less than 50%, preferably less than 30% of that of the compound A. In particular, some exemplary compound inhibition rate values are as follows: Table 3. 30 uM inhibition for hERG | Compound ID A 163 001 Inhibition for hERG (30 J) 27.10% + 1.74% 8.73% + 1.37% 5.09% + 2.43% As can be seen from Table 3, the compounds disclosed herein have low inhibition rates for human hERG while have significant superiority to the compound A, Test Example 4. Determination of time-dependent inhibition (TDI) data of the compounds disclosed herein This study was intended to investigate the time-dependent inhibition effect of the compounds on CYP3Ad4in human P450 superfamily, The mixed human liver microsomes used in this assay were purchased from Corning (USA). The test compounds were co-incubated with the human liver microsomes and a probe substrate midazolam (CYP3A4), and the concentration of the test compounds was set at 30 pM. The reaction was initiated by adding coenzyme NADPH, and terminated by adding acetonitrile dossolved with internal standard in advance. After the proteins were precipitated, the supernatant was centrifuged. The characteristic metabolite 1-hydroxy-midazolam (CYP3A4) in the supernatant was analyzed by LC-MS / MS. The influence of the test compounds on production of the characteristic metabolites was finally analyzed on the basis of the data obtained. A selective inhibitor (verapamil for CYP3A4-M) was used as positive control. Results show that the compounds in the examples of the present invention have no significant time-dependent inhibition on human CYP3A4. In particular, TDI values of some exemplary compound are as follows: Table 4. Time-dependent inhibition (TDI) on human CYP3A4 at a concentration of 30 uM Compound ID TDI (3A4, 30pM) 001 3.68% 014 | +3.85% Test Example 5. Determination of plasma protein binding (PPB) data of the compounds disclosed herein The experiment is intended to determine plasma protein binding (PPB) data of the test compounds disclosed herein. In the PPB experiment, the final administration matrix contained the test compound or a reference compound with a concentration of 1 uM and DMSO with a content of 0.2%. Collecting samples in initial time: 25 pL of the matrix containing the compound was added into a blank 96-well collecting plate, and the plate was stored at -20 °C. An equilibrated dialysis device was prepared. 100 pL of buffer was added to the receiving side of the equilibrium dialysis plate. Then 100 uL of the administration matrix containing the compound or the reference compound was added into an administration side of the equilibrium dialysis plate. The prepared equilibrium dialysis plate was placed in a 37°C shaker to be shaken for 5 h at 60 rpm. Sample was prepared at the end of cultivation (5 h): Preparing sample in the receiving side: 25 pL of sample from a receiving side was taken out and placed in a 96-well sample collecting plate, and 25 pL of a corresponding matrix (blank plasma) was added for mixing; 200 uL of ACN containing an internal standard was added, shaken for 10 minutes at 600 rpm, and centrifuged at 5594 g for 15 min, Preparing sample in the administration side: 25 pL of the sample containing test compound and reference compound from the administration side was taken out and 25 uL of a blank buffer was added for mixing; 200 pL of ACN containing an internal standard was added, shaken for 10 minutes at 600 rpm, and centrifuged at 5594 g for 15 min, Preparing sample in initial time: the sample containing test compound and reference compound was re-melted at 37 °C in initial time and then mixed with the corresponding matrix (blank buffer) in the same volume (25 pL); 200 uL of ACN containing an internal standard was added, shaken for 10 minutes at 600 rpm, and centrifuged at 5594 g for 15 min. After all the samples were centrifuged, 50 uL of a supernatant was taken and added into 50 uL of ultrapure water for mixing, and the samples were sent to liquid chromatography-mass spectrometry. Results show that the compounds in the examples of the present invention have a moderate protein binding rate to plasma of human, rats and mice, and has little binding difference between species, which may even be significantly smaller than the control compound A. In particular, the PPB data for some exemplary compounds are as follow: Table 5. Plasma protein binding (PPB) data Plasma protein binding (Bound %) ay — — | Mouse |Rat Species [Human Compound I A 99.02 013 80.90 001 81.00 163 81.66 016 86.90 85.18 86.99 76.20 81.70 79.90 84.70 83.78 80.59 87.70 90.10 Test Example 6. Inhibition of cytokine TNF-a release in LPS-induced Balb / c female mice by the compounds disclosed herein Procedures Female Balb / c mice were randomized into groups, each containing 4 mice, including a control + vehicle group, a model +vehicle group, a model + reference group and model + compound groups. The control animals received an intraperitoneal injection of normal saline (10 mL / kg) and the model animals received LPS stimulation (Sigma CAT# L2630, i.p., 10 mL / kg, 0.2 mg / kg). To the test compounds, DMSO, Solutol and 10 mM PBS were sequentially added to prepare a solution or suspension of required concentration for administration. For the vehicle, DMSO, Solutol and 10 mM PBS were mixed in a volume ratio of 5:15:80. The animals were administered through oral gavage (10 mL / kg) 16 h before LPS (or saline) stimulation at predetermined doses, and euthanized with CO; at 1.5 h after the stimulation for cardiac blood collection. The whole blood was not anticoagulated, incubated in wet ice for 1.5 h, and centrifuged at 2000 x g at 4 °C for 10 min to separate the serum. Serum was frozen at -80 °C for TNF-a assay. Quantification of TNF-a was done by TNF-a ELISA kit according to the manufacturer's instructions. The readings of absorbance at A450 were measured with a microplate reader SpectraMax i3x (Molecular Device) for calculating the inhibition of the compounds, and ICso was calculated with GraphPad Prism 7.0 software. Test results show that the compounds in the examples of the present invention have significant inhibitory effect on cytokine TNF-a release in LPS-induced Balb / c female mice, and the inhibition rate is greater than 50%, preferably greater than 70%. In particular, some exemplary compound inhibition rate values are as follows: Table 6. Inhibition rate of cytokine TNF-a release in LPS-induced Balb / c female mice 76.29 74.00 71.56 Compound ID Inhibition rate (%) of TNF-a 013 7629 001 7400 [163 71.56 ot Tn Test Example 7. Determination of inhibition of five major CYP450 enzyme subtypes in human liver microsomes by the compounds disclosed herein This study was intended to investigate the inhibitory effect of the test compounds on 5 major enzymes in human P450 superfamily, CYP1A2, 2C9, 2C19, 2D6 and 3A4-M. The mixed human liver microsomes used in this assay were purchased from Corning (USA). The test compound (compound 14) was co-incubated at 7 concentrations with human liver microsomes and five probe substrates (phenacetin for CYP1a2, diclofenac for CYP2C9, mephenytoin for CYP2C19, dextromethorphan for CYP2D6, midazolam for CYP3A4-M, mixed). See the table below. The reaction was initiated by adding coenzyme NADPH, and terminated by adding acetonitrile containing internal standard. After the proteins were precipitated, the supernatant was centrifuged. The characteristic metabolites in the supernatant (acetaminophen for CYP1A2, 4-hydroxydiclofenac for CYP2C9, 4-hydroxymephenytoin for CYP2C19, dextrorphan for CYP2D6, 1-hydroxymidazolam for CYP3A4-M) were analyzed by LC-MS / MS. The influence of the test compounds on production of the characteristic metabolites was finally analyzed on the basis of the data obtained. A selective inhibitor (ketoconazole for CYP3A4-M) may be used as positive control. Test Example 8. PK of the compounds disclosed herein in rat The rats used for pharmacokinetic study in the preferred example in the present invention were male SPF-grade SD rats (B&K Universal, Shanghai). Route of administration: a single dose by oral gavage or intravenous injection Sampling points: 0.083 h, 0.25h, 0.5h, 1h, 2 h, 4 h, 6 h, 8 h and 24 h after administration Sample processing: 0.2 mL of venous blood was collected, and let stand on ice before centrifugation to separate plasma (centrifugation conditions: 8000 rpm, 6 min, 4 °C). The separated plasma was stored at -80 °C before analysis. Internal standard working solution: An appropriate amount of tolbutamide internal standard stock solution at 645,000 ng / mL was added into a volumetric flask, and was diluted to the volume with methanol. The solution was well mixed to give an internal standard working solution with a concentration of 50 ng / mL, Sample pretreatment: 50 uL of plasma was added into a 1.5-mL centrifuge tube, and added with 250 pL of internal standard solution (methanol of the same volume for the blank control). The solution was well mixed by vortex, and centrifuged for 5 min at 14000 rpm. 200 UL of the supernatant was transferred into a 96-well sample feeding plate, and loaded onto a LC-MS / MS system. LC conditions: Column: ACQUITY UPLC BEH C18 1.7 um (50 mm x 2.10 mm) Mobile phase: A: 0.1% aqueous formic acid; B: 0.1% formic acid in acetonitrile Flow rate: 0.5 mL / min The data processing system was Analyst software (Applied Biosystems, USA, ver 1.5.5). Results show that the compounds in the examples of the present invention have good pharmacokinetic characteristics on mice, show excellent exposure and retention time in animals, and have suitable half-life and good drug absorption. In particular, pharmacokinetics data of some exemplary compounds are as follows: Table 8. Pharmacokinetic study data for single oral gavage dosing of different compounds in ICR mice PK for oral gavage | Time | Peak Area Area |compound| Dose | Formulation to 3 under under oF I Average Half i | life time to i concentration] peak | tua | Cmax AUCo: | AUCos | tiz | MRT Formulation (h) | (ag / mL) |(ng / mL*h)|(ng / mL*h)| (h) | (h) No. ’ peak | 1 curve curve | | time Dose Fomilation tmax Crnax AUCox | AUCo» | tiz | MRT (mpk) (hy | (ng / mL) |(ng / mL*h)|(ng / mL*h) (h) (h) 15%solutol 42 70501Ut01L 163 | 40 | TOC 4 25875 | 206683 | 206702 |3.62| 6.75 | 206683 | 206702 | 3.62] HS15+835%PRBS 15%solutol 47 70501401 001 | 40 | _ CUTUCC 4 24153 | 293784 | 375482 [11.47 15.31 | 293784 | 375482 [11.47 HS15+835%PRBS 15%solutol 013 | 40 | | SUSE 18924 160198 | 182133 [7.23] 1041 The examples of the present invention have been described above. However, the present invention is not limited to the above examples. Any modification, equivalent, improvement and the like made without departing from the spirit and principle of the present invention shall fall within the protection scope of the present invention.

Claims

CLAIMS 1. A compound of formula I or a stereoisomer, a racemate, a tautomer, an isotopically labeled compound, a prodrug or a pharmaceutically acceptable salt thereof, Lo Raly N° 7 (Rn 5~ HN _ 5 N R,-W Formula I one, two or more R:

2. The compound of formula I or the stereoisomer, the racemate, the tautomer, the isotopically labeled compound, the prodrug or the pharmaceutically acceptable salt thereof according to claim 1, wherein the "(Ci-Ci2)aliphatic hydrocarbyl optionally comprising one, two or more heteroatoms" may be selected from (Ci-Cialiphatic hydrocarbyloxy, (Ci-Ciz)aliphatic hydrocarbylthio, (C1-Ce)aliphatic hydrocarbyloxy(C-Cs)aliphatic hydrocarbyl, (C1-Ce)aliphatic hydrocarbylthio(C1-Ce)aliphatic hydrocarbyl, N-(Ci-Cs)aliphatic hydrocarbylamino(Ci-Ce)aliphatic hydrocarbyl, and N,N-di~(Ci-Cs)aliphatic hydrocarbylamino(C1-Cs)aliphatic hydrocarbyl; the "5-14 membered heteroaryl or 5-12 membered heterocyclyl containing at least one N" is selected from pyridine, pyrrole, piperidine and tetrahydropyrrole; the (Ci-Ciz)aliphatic hydrocarbyl may be selected from (Ci-Ciz)alkyl, (Ca-Ciz)alkenyl and (C>-Cro)alkynyl, and preferably, the (Ci-Cio)aliphatic hydrocarbyl may be selected from (C1-Ce)alkyl, (C2-Ce)alkenyl and (C2-Cs)alkynyl; the "halogen" is selected from F, Cl, Br and I; and the "Cs.12 cycloalkyl" may be selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

3. The compound of formula I or the stereoisomer, the racemate, the tautomer, the isotopically labeled compound, the prodrug or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the Ri, R2 and R3 may be each independently selected from the following groups optionally substituted with one, two or more R: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 1-ethylethenyl, 1-methyl-2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 1-hexenyl, ethynyl, l-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl, 1-hexynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxyl, propoxy, butoxy, pentyloxy, methoxymethyl, ethoxylmethyl, propoxymethyl, methoxyethyl, ethoxylethyl, propoxyethyl, methoxypropyl, ethoxylpropyl, propoxypropyl, N-methylaminomethyl, N-methylaminoethyl, N-ethylaminoethyl, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, amino, N,N-dimethylamino, N,N-diethylamino, tetrahydropyrrolyl, piperidinyl, pyridyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, = Xo 3 NOH HOE OSL en HOKE \ CN LF 4x Yc OH i —OH " Pa EF Ff OH x on \ Va A 3CF AF +x F F CF vo OH = oH 5\ OH 3 Xo HO — ! TO (A += IN 3 Ks and l TE TNL OH OH N-§ =~ =~ SN i ’N MS ad and the nén denotes the connection site of the group.

4. The compound of formula I or the stereoisomer, the racemate, the tautomer, the isotopically labeled compound, the prodrug or the pharmaceutically acceptable salt thereof according to claims 1-3, wherein in the compound of formula I or the stereoisomer, the racemate, the tautomer, the isotopically labeled compound, the prodrug or the pharmaceutically acceptable salt thereof, the compound of formula I may be selected from the following structures of formula Ia, formula Ib, formula Ic, formula Id and formula Ie: A / AS A | + Oo » oO ro (Rai NAN (Rin AN =N R,-W wn Ye i O HN = Rp-W N formula Ia formula Ib AS N™ °F 3 (Ral KAP N-R4 O~ HN = Rin O~ HN _ Sw N =, ) R,-W N R,-W N formula Ic formula Id x1) 0 + 2 Ry N">¢ N-R4 O HN _ = A R,-W N formula Ie in the formula la, formula Ib, formula Ic, formula Id and formula Ie, Ri, R2, R3, m, n and W are as defined in formula I.

5. The compound of formula I or the stereoisomer, the racemate, the tautomer, the isotopically labeled compound, the prodrug or the pharmaceutically acceptable salt thereof according to claims 1-4, wherein the compound of formula I may be selected from the following structures: H Ol 001 002 2 N+ 0 & HN - = I ~o N . 001 Sr 4 RX 002 wei Woe 7 | Z > HN = OH & uN = OH SER" Ope OR 003 004 ~ ~ uo ue @ Q Sy “he - HN 2 Oil - HN 2 On JE Da J (Hs 005 006 AN pn LI vx » x V . “ 4 0 SAA Sy oe il pe 0 H of 07 v 008 So ” Ce JK wl Vi 008 I o10 Lhe 3 OH ou e ind Bs ~ = N I oto ON 011 p12 Ye < | § H © HN. = OH JOR Vo ON Cl Sr © HN. = OH JOR ! on PN 7 | o Z o ” H "HI TT yon” I yo 013 014 — AN 015 016 ~ ae Loe & HN ) J 016 Pay Zz “7 & HN. HN a. Tom rm CRO 015 016 2N A MoH oH 017 018 016 7 "HN H JR g 018 ~ cd Se & HN. 00 017 AN Yeo JC Toh Yeon AA y i Lon A a sg 019 - 020 021 022 * 018 4 “She & - C - = ne vO 021 ¥ 2 Sh 0 & HN. = ! 022 NG 023 024 CI "HI ! 024 LI SA & & HN, = Sm Den, Tm 025 026 pe AN y o & "Cr ( = OH ~ NI J ey ~~ 027 028 Ay AN 027 028 7 Cu hn = OH ~ H = J Dy J 020 030 AN a 029 030 C1] LI Sh 5 Em bu x 89 ( =\ uy, NI ve 031 v vo 032 v 031 . Vo 2 7 oo z She Le "HN & HN = OH = ARI KE 033 I 034 & HN LE 034 ay Vv os 1 034 = | 2 > HN = OH " H = Smee Ime 1 035 | 036 CY . ~ 1 035 I 038 @ = FN = FE bom JR" 2 037 038 A “3 si 03g 7 | Zz I - HN _ i "HN. = Xe OR KR 039 040 o TY xP Y s HN. = OH Th Xe-X xm 041 AN ANA 041 042 C1 2] Che Py ” HN. "HI Lac 7 > | 0 N* i | J ( 044 A 043 044 7 ] 2 J ng® < | : > HN. wl = OH © HN. in Pn ASTRON" Ee 045 46 AN AN \vd B 047 048 C1 Oe Se - HN 2 or JO A, TH "EE 1 ve =N Vv 049 050 v 049 050 7 | 2 ” HN. = OH - HN = pe ) BO - 051 052 ~ Le C | vy ed Hy und ye bd NA rl 1 KK 053 Vv 054 Cl : SR AN Cl ” Hl SI He I oss 20, 057 1 oss 7 Loe H a > HN, OH I oss Ay I oss ' oss i Zz EF Se oe Loe 4 H on ME LRM Tx 1 os7 1 ose a 2 i” - ar J soko o_o Nar OH re OH J ORT Ie OR | 058 1 080 FY ZN 1 059 I 080 A ~ "HN. 2 1 i» XT Fe 081 082 ON N 081 062 hy 3 & HN woes X00 rn Sy 063 " - 084 wih HN. H TI pa 084 AN Yon 083 © 084 C] Ae Le "BN = '& uN Dome ro TE 065 066 CIN ON, N a. 0” N° sO mn 2 Dea 066 Aa 065 - 066 Z CR Sy " H = 4 uN 2 TOE Jon ey 087 0688 F & HN. = BG o- oes ON HoH 069 070 087 C] "HN. TT 069 Rel YoH MoH 2 H J 072 7 SAA ' bon oa or AY) om oo gd HoH CR " ” fm Jon er v oR Vv wi _ Vv 074 F. Se 0 Zz & whe TE re OE 075 id a 078 Jeon oH o 075 » 076 Z | Z ~ LI | hon ( >= Pr Ni OH = 2 or a og “SN 079 " 0BO . 077 wv 078 7” 7 "HN - H SIE pe LE om "om AY a 7 odo N CORO "om ON oH 081 ' os2 , 079 Cl ~S & HN. = po y 081 AN H SR C Yon AY MoH oH 083 I o84 4 Ae * HN oH J I oss AN 081 2 SN SNP 4 mn I” J I oss 7 CL Soh N N & Tog 085 086 ~y C N* SR 0 SEO “oom 087 088 AN AN 087 088 Cl CT YA AA " HN. " HN. J ogy J 08g 090 AYA PS Shee Os AY 2 091 2 092 Py 4 & “or HN Sy 0 ~o Sd ee, XE 083 ‘ 9 AAR < ~ 084 A 095 oo 098 093 084 2 We LI & HK = OH § s HN. ~SORHOG OE 095 096 aa Th Co Vv oO . a. v or I ( Vv or - 098 2 7 TE OR v 100 - 099 Zz We AA Len on 6 Maa IEG KR -. v 101 102 7 S, 0 & HN, = a F’ v HN. 103 T 10e 103 2 ” H i 105 AY Zz so) 0 H LI & M i oa: OH 7 RO, V 108 AN 10° 7 ’ 108 © 108 J 108 “1 Z oA Loe XE Tye T &mN i SN nl Vv JE 107 Taos AN PR 7 Le | 7 ¥ HN. 7 RE OA ! 108 ON OH 109 110 | & 10 ON 7 | - Lhe " HN. = A JI 109 2 he Lhe & én i” mm 112 113 NJ 114 7 AN & HN _ Oh JR OR () 13 A oy OH Siy s , & uN & = H GOR NA 114 ANG H Ol 115 N= 48 ~ oY Loe & HN. ~ 52 15 4 "© H FR mH == 116 117 NN qs Ae Sy 0 & H _ OH 4 17 2) 7 H & HN 2 om a 18 AY. She z | § "Yr CO hr ( o34 19 ’ nL 120 20 0 AN we A 7 Sew N H & uN 2 IE J in 21 <o Z LI & HN _ , ey : 121 Ll, NS 121 NS 12 Zz ] Zz “he Shee "HN = oH "HN, = ey Ds 1 JO ! 123 < 124 x 123 0 124 @ ~ * py = OH & & 125 L 126 AY fo Zz Loe Cl 3 HN " Sr AJ ron ATE 127 120 AN AN 1 29 “mr 130 127 128 7 7 " HN "HN. A JOE ron CICK, 129 A 130 A a Loe & uN OH JE A 130 Yeon 131 NN 432 7 Ade & HN JE J 131 A SEs Sn & uN =OH = I gm AC YoH 133 N=! 134 7 PONE g & HN Sm 7 2, x AY oH Not 133 2 “he ” HN. < 135 AN 7 Loe & uN YEN =N a 138 AY Yeoh 135 DERE] Pew > J & ee ( SA Py Soo 137 w= 4a Y=oH 139 Ww) 140 “7 Loe & HN _ oy ug 139 AY Ci A H HN. » TY x J 140 AN bal 141 N=0 142 he 139 7 Se & HN = as “ 141 AY LI N+ 0 "OR Na = 9 142 AN Joh 143 NO q44 he 141 7 Ad ’ SR ( TE © 143 SAA 9.) N OH & JO Ne Sw 9 144 AN AN 145 © 4s Zz ] @ HN = OH i. = AJR) "C el IE 147 NJ 1s AN AN ~ EEE 4H hon =N v 148 LL > 0 147 - Nd 148 d ] “ | HN = XT het So N N A 148 v & 150 2. NO AN 2 OH Y “7 149 oo 150 Zz Loe 7 ] Lene TIE Nu b = pros Sg ICR i 151 &r 2 2. jal 0 aw 151 N= 82 z & kee Lhe & nN bu = OH = & 153 Ch 154 Qi. AN N+ 1 = 153 EN 154 Pow 2 ? OE Ye “ye =. in " H -— wy py COE Py © me r OH y ~7 157 x iss Se H & HN 7 ey 185 TEN se 21 yy 0 SA dh = OH & uw GES 5S | 157 & 158 159 =O 480 2 Lhe OH ~ HN, = OH v JOR on 9 160 v Ll. Zz Sl - & nN A, on NS 159 2, Zz Zz | SA i p Sn "i = OH = OH *: TODO, aOR is v S «© 161 «© 162 Z 1. Rn L 4 Fel 161 oo 162 2 <n 0 Z & ee ji 0 l— OH © HN, SoA Be “1 SN 0 & HN. Xx ~ ~o 3) fi 164 165 166 “1 yr 0 SS ¢9 . Ao =n . 166 ve 2 2 oH HNN ~ JE - 168 L 167 168 Lhe Ah AAT 27 hy \ PH A a & HN an 169 170 LSAT LL N+ 0 & HN, Si 171 172 L A 173 174 175 ow 176 OH i If 2 Sy 0 & HN i» 175 ~~ Sr | & Hi “OR ( “Yeo 176 0 ON 177 N 178 Sy 0 & HN IE 178 i Tw N 7 he HK = OH Te 4 x 177 nN ANG SCR Ro) mo Lhe o on hd OH : Kd N 181 N 182 HN SAA y IN oo LK) w( 2 & HN. = i 184 183 . 184 C1 SN] A 4 un TNO y IB 185 i 186 185 : 186 Loo Sr & uN bw XE 20 187 188 ON ON 187 188 C0 7 - HI ~ HN. Joo LE 189 190 A AN 189 190 d 7 ~ HN. " HN one hen 191 182 ON Ter - 193 Vv 194 & HN & mn JOR SR Fr. 3 1 A008 195 198 7 | - Al ” HN. SOR 198 7 cd > HN = OH HI ~ i PRO TIE VY w 1 tes A Ih ON 199 200 A Se & HN Spon 200 NS Q HA Lhe "HN, J On 199 AY 201 202 2 199 x " HN. TT Olen 201 AN Z Sy 0 H "HN = E04 202 ON 203 204 Se & HN. Oe 203 AN cd H & HN, el On 204 LI, vx 2 \ nO LL Ton 206 ~ ul 205 Vv 206 205 Sel Sng & mn 2] ye 0 "HN. OH J O—om ' 208 AN 209 1 210 - 207 ' 208 2] Se A Se & “Cr v ol mg >on = ~\ N JE 209 I 210 7 N & HN. = on | Vee I 210 21 & HN. = - 21 ON ¥ HN. = OH TEX 212 213 214 21 C212 Z <M oo Zz 0” °N a) 0 Yodan Cl = OH & A Tr 0 Ao =N 213 214 _.n NG “1 i = OH TNR 214 AN 7 o cd She LI & ' 4 un 215 218 AN BR YuoH 2 <n Xs] & HN. = 217 ON ER en AN Yon °C CY N( Yeon nN 219 220 217 218 2 Zz oS o Le & uN — & HN Iw Yon 0 So N Ao =N 219 220 ON _ Cl N+ 0 & nN H G9 Ao =N 220 ON Yon 221 222 <19 «gd < | Se & uN _ JT 221 AN C1 JI Yon 222 ON r T\,\OH \ 223 224 ZF &H z - JI 223 > 224 £ OH 3 225 - 226 ~ Ba ~ HN - XE 225 AN Se & HN. , ~JORM > A “Ly “40 “ A SA Ah "HN * HN. 0g ion-og 227 228 A IN “HoH ll 5 HN. > - JEM 229 & JR ( Po} 231 w 232 229 N 230 2 FY Loe HN 2, \OH v Wy SR 8 fo 231 N 232 LX, Sy 0 H & HN, 2 Bil Tao A 232 W a Sr ” HN. J OS 233 i —— A Sy 0 wow = \OH JIT 3 234 J OH + I 235 2368 233 N 234 Cl Yr Sr TO TE ~o SN ol 235 238 ~ C1 238 : OH + IN 237 238 2 oO Sn 0 ! & HN = go JEM 237 7 5 0 H " HN NN Ao N 238 239 240 7 She N* C & HN. = OH | JO 239 AN vy > Sy 240 ON 241 242 Pe er 7 | o Lhe " HN. JO 241 243 Le z & HN 2 . Lhe JC Con & Xmen 244 243 a AN 2 “83 ” Ce Lo or TY Jp Omen IT Omkeon 245 248 A PN xX XE & uN - LE £59 LA N & uN - l—{ “Xo NAT 247 248 x x 247 “7 YY & HN. = — JIN 240 249 250 2 3, 0 N oH & HN - ; 250 x x 249 7 | © HI - ARH 251 252 7 Ae ” HN. - TT 252 Y—oH 2 yr 0 "© HN. ST ST GRR 253 254 Sh & HN, i” TT 264 roo TEEN yo 9 2] a & HN, > — J ARR 255 256 & HN. 1 = OR 256 tO HN rou YT TPE Yon 257 258 255 7 Se 0 & HN = oN AIR 257 7 0 Sy gS wm! “Oe No =N 258 Pal (OL \ SI | 4H ho 7 7 JI = &9f 2 Sa? ie — No =N SRO x xX 59 LX, x, 0 oO” °N ! & HN = AR C1 & HN. H = NG 4 261 282 £01 202 “7 2 Sh A & HN. HN. # =" OH = JI Pat de : 28% 284 263 264 bs 1 Sy yh " Co 265 266 N’ XE i Ao ot 267 288 5 Le 7 ¥ HN. A = AIR 269 270 nN (ad Sew & HN, J = LKR 271 2712 7 LI NAN OH & HN TR Yr ® Se Na 273 274 SA She & én = - IH OR KR 275 278 7 LA & mn QQ STO 0 "HN, = JE r-O—on 217 278 7 FWY & HN, Re OH J J & HN, CRO 280 279 280 &I9 &0U 2 Cl ji + 0 9 3 0 © HN, HI ATO IIo 281 282 281 282 7 cd Khe Lhe EL = "HN, oT = > JL 283 284 7 LA CTE ~o = 284 x 285 286 283 284 21 SN 0 C y 0 & HN ¥ = Hi Xo = ~o N ya 285 286 Lhe > Seay 286 TRO 00 AN x 289 290 7 | - HI » OR > 290 A LN J on AN [ dd ul | Sw 0 [N° & HN & un < > = Nine ge! OH J ( DS vv “o N 201 202 on method for the compound of formula I or the stereoisomer, 6. A preparation method for the compound of formula I or the stereoisomer, the racemate, the tautomer, the isotopically labeled compound, the prodrug or the pharmaceutically acceptable salt thereof according to claims 1-5, wherein the preparation method comprises: oid 5 M2 (Ro)” “N"N\2¥ Reba SA (Reh “N"COOH & 0 2) HN \ we (Ra) ¥ Rb Rol? WP N0 Rp-W N -> oy Q ©" HN 2” H N = MN N TO Ri Row H RW N M1 M3 formula | reacting M-1 and M-2 to give M-3, wherein the reaction may be performed in the presence « M1 M3 formula | (al) reacting M-1 and M-2 to give M-3, wherein the reaction may be performed in the presence of EDCILHCI and pyridine; and (a2) reacting M-3 and R«L,, wherein Ry is selected from R, and a group of R, having hydroxyl with the hydroxyl substituted with © O" ; when Ry is a group of Ry having hydroxyl with the PF Hoe, Oo Ho hydroxyl substituted with =~ O” | the reaction requires to be performed in the presence of an acid and a reductant ro give the formula I, wherein the acid may be HCI, and the reductant may be sodium borohydride; Ri, Ra, R3, m and W in the above steps are as defined in formula I, the L, is a leaving group and may be selected from halogen and -OTs.

7. A preparation method for the compound of formula I or the stereoisomer, the racemate, the tautomer, the isotopically labeled compound, the prodrug or the pharmaceutically acceptable salt thereof according to claims 1-5, wherein the preparation method comprises: ro Pooon 3 —_ JJ NMR A sy ON a HN : CNR [NR Ro-W' N — T™ RW N ON R - Rp-W' N N-1 N-2 N-3 (bl) reacting N-1 and R«Li, wherein Ry is selected from R; and a group of R| having hydroxyl with oO Ho the hydroxyl substituted with =~ O° ; when Rx is a group of Rj having hydroxyl with the Oo oy hydroxyl substituted with © 07 | the reaction requires to be performed in the presence of an acid and a reductant to give N-2, wherein the acid may be HCI, and the reductant may be sodium borohydride; (b2) reducing the N-2 obtained in the above step to give N-3, wherein a reductant may be Pd / C; and (b3) reacting the N-3 and M-2 to give the formula I. Ri, R2, R3, m and W in the above steps are as defined in formula I, the L; is a leaving group and may be selected from halogen and -OTs, 8. A pharmaceutical composition comprising the compound of formula I or the stereoisomer, the racemate, the tautomer, the isotopically labeled compound, the prodrug or the pharmaceutically acceptable salt thereof according to claims 1-5.

9. Use of the compound of formula I or the stereoisomer, the racemate, the tautomer, the isotopically labeled compound, the prodrug or the pharmaceutically acceptable salt thereof according to claims 1-5 or the pharmaceutical composition according to claim 8 in preparing a medicament for preventing and / or treating diseases or disorders mediated by IRAK.

10. The use according to claim 9, wherein the diseases or disorders are selected from tumors, gout, systemic lupus erythematosus, multiple sclerosis, metabolic syndrome, atherosclerosis, myocardial infarction, sepsis, inflammatory bowel disease, asthma, rheumatoid arthritis, allergy, and the like.