Prmt5 inhibitors and uses thereof

Abstract

Compounds and compositions for modulating or inhibiting PRMT5 are provided.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480037034.X (22) Application Date 2024.05.31 (66) Domestic Priority Data PCT / CN2023 / 098094 2023.06.02 CN PCT / CN2023 / 133986 2023.11.24 CN PCT / CN2024 / 071562 2024.01.10 CN PCT / CN2024 / 091509 2024.05.07 CN (85) Date of PCT International Application Entering the National Phase 2025.12.02 (86) Application Data of PCT International Application PCT / CN2024 / 096753 2024.05.31 (87) Publication data of PCT international application WO2024 / 245412 EN 2024.12.05 (71) Applicant: Insil Intelligent Technology Intellectual Property Limited Address: 26 / F, Tower 3, Exchange Square, 8 Connaught Place, Central, Hong Kong (72) Inventors: Ding Xiao, Ding Xiaoyu, Lu Hongfu, Ren Feng, Zhang Meng (74) Patent Agency: Beijing Zhongzi Law Firm 11247 Patent Attorneys: Jia Shicong, Huang Gesheng (51) Int.Cl. C07D 471 / 04 (2006.01) C07D 471 / 14 (2006.01) C07D 495 / 04 (2006.01) C07D 491 / 048 (2006.01) A61K 31 / 55 (2006.01) A61K 31 / 519 (2006.01) A61P 35 / 00(2006.01) (54) Invention Title: PRMT5 Inhibitor and Use Thereof (57) Abstract: Compounds and compositions for regulating or inhibiting PRMT5 are provided. Claims (10 pages), Description (206 pages), CN 121285551 A, 2026.01.06, CN 1 21 28 55 51 A 1. A compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof: Formula (I) Wherein: Ring A is a 4- to 7-membered cycloalkyl or a 4- to 7-membered heterocycloalkyl; R4 are each independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O) NRcRd, ‑NRbC(=O)Ra, ‑NRbC(=O)ORb, ‑NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)R, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R4a; or two R4s on the same atom together form an oxo group; or two R4s on the same atom together form a cycloalkyl or heterocycloalkyl group; each of which is optionally substituted by one or more R4b; each of the R4a is independently halogen, -CN, -NO2, -OH, -OR a,‑OC(=O)Ra,‑OC(=O)ORb,‑OC(=O)NRcRd,‑SF5,‑SH,‑SR a,‑S(=O)Ra,‑S(=O)2R a,‑S(=O)2NR cRd,‑S(=O)(=NRb)Rb,‑NRcRd,‑NRbC(=O) NRcRd,‑NRbC(=O)Ra,‑NRbC(=O)ORb,‑NRbS(=O)2R a,‑N=S(=O)(Rb)2,‑C(=O)R a,‑C(=O)ORb,‑C(= O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R; or two R4a on the same atom together form an oxo group; R4b are each independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NR cRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl-L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently and optionally substituted by one or more Rs; or two R4b on the same atom together form an oxo group; n is 1, 2, 3, 4, 5, or 6; R5 is -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2- C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R5a; each R5a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2R a、-N=S(=O)(Rb)2、-C(=O)R a、-C(=O)ORb、-C(=O)NRcRd、-P(=O)(Rb)2、C1-C6 alkyl、C1-C6 haloalkyl、C1-C6 hydroxyalkyl、C1-C6 aminoalkyl、C1-C6 heteroalkyl、C2-C6 alkenyl、C2-C6 ynyl、-L-cycloalkyl、-L-heterocycloalkyl、-L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R; or two R5a on the same atom together form an oxo group; W is N or CRW; RW is hydrogen, halogen, -CN, -NO2, -OH, -OR a,‑OC(=O)Ra,‑OC(=O)ORb,‑OC(=O)NRcRd,‑SF5,‑SH,‑SRa,‑S(=O)Ra,‑S(=O)2R a,‑S(=O)2NR cRd,‑S(=O)(=NRb)Rb,‑NRcRd,‑NRbC(=O)NRcRd,‑NRbC(=O) Ra,‑NRbC(=O)ORb,‑NRbS(=O)2Ra、-N=S(=O)(Rb)2、-C(=O)R a、-C(=O)ORb、-C(=O)NRcRd、-P(=O)(Rb)2、C1-C6 alkyl、C1-C6 haloalkyl、C1-C6 hydroxyalkyl、C1-C6 aminoalkyl、C1-C6 heteroalkyl、C2-C6 alkenyl、C2-C6 ynyl、-L-cycloalkyl、-L-heterocycloalkyl、-L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R; U is N or CRU; RU is hydrogen, halogen, -CN, -NO2, -OH, -OR a、-OC(=O)Ra、-OC(=O)ORb、-OC(=O)NRcRd、-SF5、-SH、- SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2- C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently and optionally substituted by one or more R groups; T is N or CRT; RT is hydrogen, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NR cRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)R a, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R; X is C and Y is C;X is C and Y is N; or X is N and Y is C; Z1 is O, S, N, NR1a, CR1b or C(R1c)2; Z2 is O, S, N, NR2a, CR2b or C(R2c)2; Z3 is O, S, N, NR3a, CR3b or C(R3c)2; R1a, R2a and R3a are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R; R1b, R2b, and R3b are each independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently and optionally substituted by one or more R; R1c is each independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6... Haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently and optionally substituted by one or more Rs; or two R1cs together form an oxo group; each R2c is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, - L-heterocyclic alkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl group is independently and optionally substituted by one or more R groups; or two R2c groups together form an oxo group; R3c groups are each independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6The alkyl group is a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, an -L-cycloalkyl group, an -L-heterocycloalkyl group, an -L-aryl group, or an -L-heteroaryl group; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently and optionally substituted by one or more R groups; or two R3c groups together form an oxo group; Ra is each independently a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, an -L-cycloalkyl group, an -L-heterocycloalkyl group, an -L-aryl group, or an -L-heteroaryl group, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently and optionally substituted by one or more R groups; Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently and optionally substituted by one or more R; Rc and Rd are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6... Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heteroalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heteroalkyl, aryl, or heteroaryl is independently and optionally substituted by one or more R; or Rc and Rd together with the atoms to which they are attached form a heteroalkyl group, which is optionally substituted by one or more R; L is absent or is a C1-C4 alkylene group optionally substituted by one or more R; and each R is independently a halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, - NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl)2, -O-C1-C4 alkylene-OH, -O-C1-C4 alkylene-NH2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl or 3 to 6-membered heterocyclic alkyl; or two Rs on the same atom forming an oxo group. 2. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of formula (I) has formula (Ia): Claims 3 / 10 page 4 CN 121285551 A Formula (Ia) Wherein: Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R6 are each independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2R a, -N=S(=O)(Rb)2, -C(=O)R, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R; or two R6s on the same atom together form an oxo group; m is 0, 1, 2, 3, 4, 5 or 6; R7s are each independently halogenated, -CN, -NO2, -OH, -OR a、-OC(=O)Ra、-OC(=O)ORb、-OC(=O)NRcRd、-SF5、-SH、-SR a、-S(=O)Ra、-S(=O)2R a、-S(=O)2NR cRd、-S(=O)(=NRb)Rb、-NRcRd、-NRbC(=O)NRcRd、-NRbC(=O)Ra、-NRbC(=O)ORb、-NRbS(=O)2R a、-N=S(=O)(Rb)2、-C(=O)R a、-C(=O)ORb、-C(=O)NRcRd、-P(=O)(Rb)2、C1-C6 alkyl、C1-C6 haloalkyl、C1-C6 hydroxyalkyl、C1-C6 aminoalkyl、C1-C6 heteroalkylThe alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl groups are optionally substituted independently by one or more R groups; or two R7 groups on the same atom together form an oxo group; p is 0, 1, 2, 3, 4, or 5; and L is absent or is a C1-C4 alkylene group optionally substituted by one or more R groups. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each of R6 is independently a halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -NRcRd, -C(=O)Ra, -C(=O)ORb, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R. 4. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the ring is [missing information]. 5. The compound of claim 2 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is CN 121285551 A (page 4 / 10 of claim). 6. The compound of claim 2 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is or the compound is. 7. The compound of claim 2 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is CN 121285551 A (page 5 / 10 of claim). 8. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of formula (I) has formula (Ib): Formula (Ib) wherein: the ring C is a cycloalkyl or heterocycloalkyl group; R6 is each independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(= O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkylThe alkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl groups are substituted independently and optionally by one or more R groups; or two R6 groups on the same atom together form an oxo group; m is 0, 1, 2, 3, 4, 5, or 6; Claims 6 / 10, page 7, CN 121285551 A. Each R7 is independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NR cRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2R a, -N=S(=O)(Rb)2, -C(=O)R a, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R; Or two R7 atoms on the same atom together form an oxo group; q is 0, 1, 2, 3, or 4. 9. The compound of any one of claims 1-8 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is a 4- to 6-membered cycloalkyl group. 10. The compound of claim 9 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is a 4- to 6-membered fully saturated cycloalkyl group. 11. The compound of claim 9 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is a 4- to 6-membered partially saturated cycloalkyl group. 12. The compound of claim 11 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is , or . 13. The compound of claim 11 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein or . 14. The compound of any one of claims 1-8 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is a 4- to 6-membered heterocycloalkyl group. 15. The compound of claim 14 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is a 4- to 6-membered fully saturated heterocyclic alkyl group. 16. The compound of claims 1-5 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is , , or .17. The compound of claim 1-5 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R7 is or is defined in claim 7 / 10, page 8, CN 121285551 A. 18. The compound of claim 14 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is a 4- to 6-membered partially saturated heterocyclic alkyl group. 19. The compound of any one of claims 2-18 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R7 is independently a halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. 20. The compound of any one of claims 2-18 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein two R7s on the same atom together form an oxo group. 21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently and optionally substituted by one or more R5a. 22. The compound of claim 21, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L is a bond or -CH2-. 23. The compound of claim 21, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is CH3, CHF2, CF3, CH2CH3, CH2CH(CH3)2, CH2CHF2, CH2CF3, or... 24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each of R5a is independently a halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; wherein the alkyl group is independently and optionally substituted by one or more Rs. 25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein W is CRW. 26. The compound of claim 25, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RW is hydrogen, a halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 aminoalkyl.27. The compound of any one of claims 1-26 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein U is CRU. 28. The compound of claim 27 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RU is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; wherein the alkyl is optionally substituted with one or more R. 29. The compound of any one of claims 1-28 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein T is CRT. 30. The compound of claim 29 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RT is hydrogen, halogen, -C1-C3 alkyl, C1-C3 haloalkyl, or C2-C3 alkynyl. 31. The compound of any one of claims 1-30 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RT is hydrogen, halogen, -C1-C3 alkyl, C1-C3 haloalkyl, or C2-C3 alkynyl. 32. The compound of any one of claims 1-30 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RT is hydrogen, halogen, -C1-C3 alkyl, -C1-C3 haloalkyl, or C2-C3 alkynyl. 33. The compound of any one of claims 1-30 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RT is a compound of any one of claims 1-30 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RT is a compound of any one of claims 1-35 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RT is a compound of any one of claims 1-35 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RT is a compound of any one of claims 1-35 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RT is a compound of any one of claims 1-35 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RT is a compound of any one of claims 1-35 or a pharmaceutically acceptable carrier or excipient. 37. A method of treating a disease or condition, the method comprising administering to an individual in need a compound of any one of claims 1-35 or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of claim 36, wherein the disease or condition is associated with overexpression of PRMT5. 38. The method of claim 37, wherein the disease or condition is cancer. 39. A method of treating cancer, the method comprising administering to an individual in need a compound of any one of claims 1-35, a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of claim 37. 40. The method of claim 38 or 39, wherein the cancer is selected from pancreatic cancer, colorectal cancer, uterine cancer, bile duct cancer, gastric cancer, bladder cancer, cervical cancer, testicular germ cell cancer, non-small cell lung cancer, multiple myeloma, diffuse large B-cell cancer, etc.Cellular lymphoma, rhabdomyosarcoma, and squamous cell carcinoma of the skin. Claims 10 / 10 pages 11 CN 121285551 A PRMT5 inhibitor and its use

[0001] Cross-reference

[0002] This patent application claims the benefit of international application No. PCT / CN2023 / 098094 filed on June 2, 2023, international application No. PCT / CN2023 / 133986 filed on November 24, 2023, international application No. PCT / CN2024 / 071562 filed on January 10, 2024, and international application No. PCT / CN2024 / 091509 filed on May 7, 2024, all of which are incorporated herein by reference in their entirety.

[0003] Background

[0004] Traditional chemotherapy drugs have extensive cytotoxicity, and many of their side effects can be attributed to their harmful effects on healthy cells. On the other hand, targeted therapies selectively target tumor cells, often leading to improved clinical outcomes. Several targeted therapies have already achieved good clinical results, such as tyrosine kinase inhibitors that target BCR-ABL tyrosine kinase, which is uniquely expressed in cancer cells. Protein arginine N-methyltransferase (PRMT5) has been identified as another potential target for selective chemotherapy, but PRMT5 inhibitors have not yet been approved for clinical use.

[0005] Protein arginine N-methyltransferase (PRMT5) catalyzes the sequential electrophilic transfer of two methyl groups from two equivalents of S-adenosyl-L-methionine (SAM) to each terminal nitrogen of the guanidine moiety of the arginine residue. This reaction produces symmetrical dimethylarginine (sDMA). In addition, PRMT5 methylates several histones to regulate gene expression. PRMT5 is a cellularly essential enzyme with a complex association with p16 / CDKN2A deletion (a common genetic feature in cancer cells). Therefore, PRMT5 inhibitors have attracted attention as selective chemotherapeutic agents.

[0006] Approximately 15% of cancer cells lack the p16 / CDKN2A gene and also lack the proximal gene encoding methionine phosphorylase (MTAP). Methionine phosphorylase (MTAP) catalyzes the conversion of methionine (MTA) to methionine. Therefore, due to reduced MTA processing into methionine, cells that do not express MTAP experience elevated MTA concentrations. Because of its structural similarity to SAM, MTA competes with SAM for the active site of PRMT5. Therefore, cancer cells lacking the MTAP gene experience enhanced PRMT5 inhibition, reduced methylation activity, and increased susceptibility to PRMT5 depletion or loss of activity. This effect makes cancer cells selectively susceptible to PRMT5 inactivation by exogenous inhibitors.

[0007] PRMT5 is essential for the survival of normal tissue cells, and research suggests that inhibiting PRMT5 in normal tissues...This can lead to serious adverse reactions, such as pancytopenia, infertility, skeletal muscle loss, and / or myocardial hypertrophy. Therefore, any PRMT5 inhibitor must exhibit very high selectivity for cancer cells. Because MTA is more concentrated in MTAP-deficient tumor cells and less concentrated in healthy cells, it is expected that MTA-synergistic PRMT5 inhibitors (inhibitors that bind to the MTA-PRMT5 complex) will target cancer cells with high selectivity. Therefore, there is a need to develop MTA-synergistic PRMT5 inhibitors.

[0008] Overview

[0009] This document discloses compounds of formula (I) as described herein, or pharmaceutically acceptable salts or stereoisomers thereof.

[0010]

[0011] Formula (I).

[0012] This document also discloses compounds of formula (Ia) as described herein, or pharmaceutically acceptable salts or stereoisomers thereof: Specification 1 / 206 pages 12 CN 121285551 A

[0013]

[0014] Formula (Ia)

[0015] This document also discloses compounds of formula (Ib) as described herein, or pharmaceutically acceptable salts or stereoisomers thereof:

[0016]

[0017] Formula (Ib)

[0018] This document also discloses pharmaceutical compositions comprising the disclosed compounds or pharmaceutically acceptable salts or stereoisomers thereof, and pharmaceutically acceptable carriers or excipients.

[0019] This document also discloses methods of treatment and methods of use, said methods comprising administering the disclosed compounds and compositions to an individual.

[0020] Incorporation by Reference

[0021] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the same extent that each individual publication, patent or patent application is specifically and individually indicated as incorporated herein by reference.

[0022] Detailed Description

[0023] Definitions

[0024] In the following description, certain specific details are set forth to provide a thorough understanding of the various embodiments. However, those skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout the specification and the following claims, the word “comprising” and its variations, such as “including” and “containing,” shall be interpreted in an open-ended, inclusive sense, i.e., “including but not limited to.” Furthermore, the headings provided herein are for convenience only and do not constitute an explanation of the scope or meaning of the claimed invention.

[0025] References to “some embodiments” or “one embodiment” throughout this specification mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment. Therefore, various places in this specificationThe phrases “in one embodiment” or “in an embodiment” do not necessarily refer to the same embodiment. Furthermore, specific features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Additionally, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly indicates otherwise. It should also be noted that the terms “or” and “or” are generally used in a meaning including “and / or” unless the content clearly indicates otherwise.

[0026] Unless otherwise indicated, the following terms as used herein have the following meanings: Specification 2 / 206 page 13 CN 121285551 A

[0027] “Oxygenated” means =O.

[0028] “Carboxyl” means -COOH.

[0029] “Cyano” means -CN.

[0030] “Alkyl” means a straight-chain or branched monovalent group of a saturated hydrocarbon having 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-ethyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, and longer alkyl groups such as heptyl, octyl, etc. Whenever it appears herein, numerical ranges such as “C1-C6 alkyl” or “C1-6 alkyl” mean that an alkyl group can consist of 1, 2, 3, 4, 5, or 6 carbon atoms, although this definition also covers the occurrence of the term “alkyl” without a specified numerical range. In some embodiments, the alkyl group is C1-10 alkyl. In some embodiments, the alkyl group is C1-6 alkyl. In some embodiments, the alkyl group is C1-5 alkyl. In some embodiments, the alkyl group is C1-4 alkyl. In some embodiments, the alkyl group is C1-3 alkyl. Unless otherwise expressly stated in this specification, the alkyl group may optionally be substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl group may optionally be substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl group is optionally substituted with a halogen, -CN, -OH, or -OMe.

[0031] "Alkenyl" means a straight-chain or branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The group may be in the cis or trans conformation of the relevant double bond and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever it appears herein, numerical ranges such as "C2-C6 alkenyl" or "C2-6 alkenyl" mean that the alkenyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, but this definition also covers the occurrence of the term "alkenyl" without a specified numerical range. Unless otherwise expressly stated in this specification, the alkenyl group may optionally be substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl group is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl group is optionally substituted by halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl group is optionally substituted by halogen.

[0032] "Alynyl" refers to a straight-chain or branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Whenever it appears herein, numerical ranges such as “C2-C6 ynyl” or “C2-6 ynyl” mean that the ynyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, but this definition also covers the occurrence of the term “ynyl” without a specified numerical range. Unless otherwise expressly stated in this specification, the ynyl group may optionally be substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the ynyl group is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the ynyl group is optionally substituted by halogen, -CN, -OH, or -OMe. In some embodiments, the ynyl group is optionally substituted by halogen.

[0033] “Alkyne” refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise expressly stated in this specification, alkylene groups may optionally be substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, or carboxylic acid groups. (Specification 3 / 206, page 14, CN 121285551 A)Ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. are substituted. In some embodiments, the alkylene group is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene group is optionally substituted with halogen.

[0034] "Alkoxy" refers to a group of the formula -Oalkyl, wherein the alkyl group is as defined above. Unless otherwise expressly stated in this specification, the alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy group is optionally substituted with halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy group is optionally substituted with a halogen, -CN, -OH, or -OMe.

[0035] "Aryl" refers to a group derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocyclic alkyl group, the aryl group is bonded through aromatic ring atoms) or bridged ring system. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a C6-C10 aryl group. In some embodiments, the aryl group is a 6-membered aryl (phenyl) group. Aryl groups include, but are not limited to, aryl groups derived from the following hydrocarbon ring systems: anthracene, naphthylene, phenanthrylene, anthracene, azurite, benzene, phenanthrylene, fluorene, as-indacene, s-indacene, indene, indene, naphthalene, phenalene, pleiadene, pyrene, and triphenylene[9,10]. Unless otherwise expressly stated in this specification, aryl groups may optionally be substituted, for example, with halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, etc. In some embodiments, the aryl group is optionally substituted with a halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl group is optionally substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl group is optionally substituted with a halogen.

[0036] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fusion (when combined with an aryl orWhen heteroaryl rings are fused, the cycloalkyl group is bonded via non-aromatic ring atoms, spirocyclic rings, or bridging ring systems. In some embodiments, the cycloalkyl group is fully saturated. Representative cycloalkyl groups include, but are not limited to, cycloalkyl groups having 3 to 15 carbon atoms (e.g., C3-C15 fully saturated cycloalkyl groups or C3-C15 cycloalkenyl groups), cycloalkyl groups having 3 to 10 carbon atoms (e.g., C3-C10 fully saturated cycloalkyl groups or C3-C10 cycloalkenyl groups), cycloalkyl groups having 3 to 8 carbon atoms (e.g., C3-C8 fully saturated cycloalkyl groups or C3-C8 cycloalkenyl groups), cycloalkyl groups having 3 to 6 carbon atoms (e.g., C3-C6 fully saturated cycloalkyl groups or C3-C6 cycloalkenyl groups), cycloalkyl groups having 3 to 5 carbon atoms (e.g., C3-C5 fully saturated cycloalkyl groups or C3-C5 cycloalkenyl groups), or cycloalkyl groups having 3 to 4 carbon atoms (e.g., C3-C4 fully saturated cycloalkyl groups or C3-C4 cycloalkenyl groups). In some embodiments, the cycloalkyl group is a 3- to 10-membered fully saturated cycloalkyl group or a 3- to 10-membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 3- to 6-membered fully saturated cycloalkyl group or a 3- to 6-membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 5- to 6-membered fully saturated cycloalkyl group or a 5- to 6-membered cycloalkenyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthyl, trans-decahydronaphthyl, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, as well as 7,7-dimethylbicyclo[2.2.1]heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise expressly stated in this specification, cycloalkyl groups may optionally be substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the cycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. Specification 4 / 206 page 15 CN 121285551 A In some embodiments, the cycloalkyl group is optionally substituted with a halogen. As used herein, "cycloalkylene" refers to a divalent cycloalkyl group as described herein. In some embodiments, when the cycloalkylene group comprises a cycloalkyl group fused with an aryl or heteroaryl ring, the cycloalkylene group...The cycloalkyl group is bonded to the cycloalkyl group and an aryl group or a heteroaryl group. In some embodiments, when the cycloalkylene group comprises a cycloalkyl group fused to an aryl or heteroaryl ring, the cycloalkylene group is bonded only to the cycloalkyl group.

[0037] "Halogen" or "halogen" means bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[0038] "Halogenated alkyl group" means an alkyl group defined above that is substituted with one or more halogenated groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0039] "Hydroxyalkyl group" means an alkyl group defined above that is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0040] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0041] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl group are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl group is attached to the rest of the molecule at the carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group consists of 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, wherein the heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group containing one or two oxygen, nitrogen, or sulfur atoms, wherein the heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group containing one oxygen, nitrogen, or sulfur atom, wherein the heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. Examples of such heteroalkyl groups are, for example, -CH 2OCH 3, -CH 2CH 2OCH 3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise expressly stated in this specification, heteroalkyl groups may optionally be substituted, for example, by oxidizing, halogenating, aminoizing, or otherwise modifying them.Nitriles, nitro groups, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, aryl groups, cycloalkyl groups, heteroalkyl groups, heteroaryl groups, etc. are substituted. In some embodiments, the heteroalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl group is optionally substituted with halogen.

[0042] "Heteroalkyl" refers to a 3- to 24-membered partially saturated or fully saturated cyclic group containing 2-23 carbon atoms and 1-8 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heteroalkyl group is fully saturated. In some embodiments, the heteroalkyl group contains 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroalkyl group contains 1-3 heteroatoms selected from nitrogen and oxygen. In some embodiments, the heterocyclic alkyl group comprises 1 to 3 nitrogen atoms. In some embodiments, the heterocyclic alkyl group comprises 1 or 2 nitrogen atoms. In some embodiments, the heterocyclic alkyl group comprises 1 nitrogen atom. In some embodiments, the heterocyclic alkyl group comprises 1 nitrogen atom and 1 oxygen atom. Unless otherwise expressly stated in this specification, the heterocyclic alkyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic system, which may include fused (when fused with an aryl or heteroaryl ring, the heterocyclic alkyl group is bonded by non-aromatic ring atoms), spirocyclic, or bridging ring systems; and the nitrogen, carbon, or sulfur atoms on the heterocyclic alkyl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. Representative heterocyclic alkyl groups include, but are not limited to, heterocyclic alkyl groups having 2-15 carbon atoms (e.g., C2-C15 fully saturated heterocyclic alkyl groups or C2-C15 heterocyclic alkenyl groups), heterocyclic alkyl groups having 2-10 carbon atoms (e.g., C2-C10 fully saturated heterocyclic alkyl groups or C2-C10 heterocyclic alkenyl groups), and heterocyclic alkyl groups having 2-8 carbon atoms (e.g., C2-C15 fully saturated heterocyclic alkyl groups or C2-C10 heterocyclic alkenyl groups). Heterocyclic alkyl groups having 2-7 carbon atoms (e.g., C2-C7 fully saturated heterocyclic alkyl groups or C2-C8 heterocyclic alkenyl groups), heterocyclic alkyl groups having 2-6 carbon atoms (e.g., C2-C6 fully saturated heterocyclic alkyl groups or C2-C6 heterocyclic alkenyl groups), heterocyclic alkyl groups having 2-5 carbon atoms (e.g., C2-C5 fully saturated heterocyclic alkyl groups or C2-C5 heterocyclic alkenyl groups), or heterocyclic alkyl groups having 2-4 carbon atoms (e.g., C2-C4 fully saturated heterocyclic alkyl groups or C2-C4 heterocyclic alkenyl groups). Examples of such heterocyclic alkyl groups include, but are not limited to, azirropropyl, azirrobutyl, oxobutyl, dioxacyclopentyl, thienyl[1,3]dithiohexyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, and isothiazolyl.Oxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolidinyl, pyrazolidinyl, quininecycloyl, thiazolyl, tetrahydrofuranyl, trithiohexyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxacyclopenten-4-yl, and 2-oxo-1,3-dioxacyclopenten-4-yl. The term heterocyclic alkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocyclic alkyl has 2 to 10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in a heterocyclic group, the number of carbon atoms in the heterocyclic group is different from the total number of atoms constituting the heterocyclic group (i.e., the skeletal atoms of the heterocyclic ring), which includes heteroatoms. In some embodiments, the heterocyclic alkyl is a 3- to 8-membered heterocyclic alkyl. In some embodiments, the heterocyclic alkyl is a 3- to 7-membered heterocyclic alkyl. In some embodiments, the heterocyclic alkyl is a 3- to 6-membered heterocyclic alkyl. In some embodiments, the heterocyclic alkyl is a 4- to 6-membered heterocyclic alkyl. In some embodiments, the heterocyclic alkyl is a 5- to 6-membered heterocyclic alkyl. In some embodiments, the heterocyclic alkyl is a 3- to 8-membered heterocyclic alkenyl. In some embodiments, the heterocyclic alkyl is a 3- to 7-membered heterocyclic alkenyl. In some embodiments, the heterocyclic alkyl is a 3- to 6-membered heterocyclic alkenyl. In some embodiments, the heterocyclic alkyl is a 4- to 6-membered heterocyclic alkenyl. In some embodiments, the heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkenyl group. Unless otherwise expressly stated in this specification, the heterocyclic alkyl group may optionally be substituted as described below, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, etc. In some embodiments, the heterocyclic alkyl group is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocyclic alkyl group is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocyclic alkyl group is optionally substituted by halogen. As used herein, "heterocyclic alkylene" refers to a divalent heterocyclic alkyl group as described herein. In some embodiments, when the heterocyclic alkyl group comprises a heterocyclic alkyl group fused with an aryl or heteroaryl ring, the heterocyclic alkyl group is bonded to the heterocyclic alkyl group and the aryl group, or to the heterocyclic alkyl group and the heteroaryl group. In some embodiments, when the heterocyclic alkyl group comprises a heterocyclic alkyl group fused with an aryl or heteroaryl ring...When the heterocyclic alkyl group is used, the heterocyclic alkylene group is bonded only to the heterocyclic alkyl group.

[0043] "Heteroaryl" refers to a 5- to 14-membered ring group containing 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl group contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heteroaryl group contains 1 to 3 heteroatoms selected from nitrogen and oxygen. In some embodiments, the heteroaryl group contains 1 to 3 nitrogen atoms. In some embodiments, the heteroaryl group contains 1 or 2 nitrogen atoms. In some embodiments, the heteroaryl group contains 1 nitrogen atom. The heteroaryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the heteroaryl group is bonded through aromatic ring atoms) or bridged ring system; and the nitrogen, carbon or sulfur atoms on the heteroaryl group can optionally be oxidized; the nitrogen atom can optionally be quaternized. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include, but are not limited to, aziridine, acridine, benzimidazolyl, and benzo[a](x) ... Thiazolyl, benzoindolyl, benzo[b][1,4]dioxepinyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxyl, benzonaphthofuranyl, benzooxazolyl, benzodioxinyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazoleyl, cenylyl, dibenzo[b][1,4]dioxepinyl, benzo[b][1,4]dioxylyl, benzo[b][1,4]naphthofuranyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]naphthofuranyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]naphthofuranyl, benzo[b][1,4]naphtho[b][1,4]dioxepin ... Furanyl, dibenzothiopheneyl, furanyl, furanoneyl, furanyl, isothiazolyl, imidazoyl, indazoleyl, indoleyl, isoindoleyl, indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthidyl, oxadiazolyl, 2-oxoazapyridine, oxazolyl, ethylene oxide, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, 1-phenyl-1H-pyrroloyl, phenazinyl, phenothiazinyl, phenotoxazinyl, phthalazinyl, pteridinyl, purine, pyrroloyl, pyrazolyl, pyridinyl, pyridinyl, pyrimidinyl, pyridazinyl Quinazolinyl, quinoxalinyl, quinolinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophene (i.e., thiophene). Unless otherwise expressly stated in this specification, heteroaryl groups may be selected.The alkyl group is substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroaryl group is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl group is optionally substituted with halogen.

[0044] The terms "optional" or "optionally" mean that the event or condition described below may or may not occur, and the description includes instances where the event or condition occurs and instances where it does not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. Furthermore, the optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). Those skilled in the art will understand that for any group containing one or more substituents, such groups are not intended to introduce any spatially impractical and / or synthetically infeasible substitution or substitution pattern. Therefore, any substituent described herein should generally be understood to have a molecular weight of at most about 1,000 Daltons, and more typically, at most about 500 Daltons.

[0045] When referring to optional substituents, the term "one or more" means that the subject group is optionally substituted by 1, 2, 3, 4, or more substituents. In some embodiments, the subject group is optionally substituted by 1, 2, 3, or 4 substituents. In some embodiments, the subject group is optionally substituted by 1, 2, or 3 substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

[0046] The term "effective amount" or "therapeutic effective amount" refers to the amount of compound that, when administered to a mammalian individual as a single dose or as part of a series of doses, is effective in producing the desired therapeutic effect.

[0047] As used herein, the terms "treat," "treating," or "treatment" include relieving, reducing, or improving at least one symptom of a disease or condition, preventing other symptoms, inhibiting a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, causing the disease or condition to regress, relieving the condition caused by a disease or condition, or stopping the symptoms of a disease or condition.

[0048] As used herein, “PRMT5-related disease or disorder” or “PRMT5-mediated disease or disorder” means any disease or other harmful condition in which PRMT5 or its mutants are known or suspected to play a role.

[0049] Compounds

[0050] This document describes compounds of formula (I), (Ia) or (Ib) or pharmaceutically acceptable salts or stereoisomers thereof, the specification of which is available on page 7 / 206 of CN 121285551 A and is indicated for the treatment of PRMT5-related diseases.

[0051] This document describes compounds of formula (I) or pharmaceutically acceptable salts or stereoisomers thereof:

[0052]

[0053] Formula (I)

[0054] wherein:

[0055] Ring A is a 4- to 7-membered cycloalkyl or a 4- to 7-membered heterocycloalkyl;

[0056] R4 is each independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2R a, -N=S(=O)(Rb)2, -C(=O)R, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted;

[0057] or two R4s on the same atom together form an oxo group;

[0058] or two R4s on the same atom together form a cycloalkyl or heterocycloalkyl group; each of which is optionally substituted;

[0059] n is 1, 2, 3, 4, 5 or 6;

[0060] R5 is -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally and independently substituted;

[0061] W is N or CRW;

[0062] RW is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NR cRd,‑S(=O)(=NRb)Rb,‑NRcRd,‑NRbC(=O)NRcRd,‑NRbC (=O)Ra,‑NRbC(=O)ORb,‑NRbS(=O)2R a,‑N=S(=O)(Rb)2,‑C(=O)R a,‑C(=O)ORb,‑C(=O)NRcRd,‑P (=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0063] U is N or CRU;

[0064] RU is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NR cRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0065] T is N or CRT;

[0066] RT is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0067] X is C and Y is C;

[0068] or X is C and Y is N;

[0069] or X is N and Y is C;

[0070] Z1 is O, S, N, NR1a, CR1b or C(R1c)2;

[0071] Z2 is O, S, N, NR2a, CR2b or C(R2c)2;

[0072] Z3 is O, S, N, NR3a, CR3b or C(R3c)2;

[0073] R1a, R2a and R3a are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently and optionally substituted by one or more R groups;

[0074] R1b, R2b, and R3b are each independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently and optionally substituted by one or more R groups;

[0075] R1c are each independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SR a, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, arylThe heteroaryl group is independently and optionally substituted by one or more Rs;

[0076] or the two R1cs together form an oxo group;

[0077] each of the R2cs is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is independently and optionally substituted by one or more Rs;

[0078] or the two R2cs together form an oxo group;

[0079] each of the R3cs is independently hydrogen, halogen, -CN, -NO2, -OH, -OR a, -SF5, -SH, -SR a, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0080] or two R3c together form an oxo group;

[0081] Ra is each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R;

[0082] Rb is each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl, wherein each alkyl group is independently substituted by one or more R; The alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are independently and optionally substituted by one or more R groups;

[0083] Rc and Rd are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently and optionally substituted by one or more R groups;

[0084] Or Rc and Rd together with the atoms to which they are attached form a heterocyclic alkyl group, which is optionally substituted by one or more Rs;

[0085] L is absent or is a C1-C4 alkylene group optionally substituted by one or more Rs; and

[0086] R is each independently a halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), - NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl)2, -O-C1-C4 alkylene-OH, -O-C1-C4 alkylene-NH2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl or 3 to 6-membered heterocyclic alkyl;

[0087] Or two R atoms on the same atom can form an oxo group.

[0088] This document describes compounds of formula (I) or pharmaceutically acceptable salts or stereoisomers thereof:

[0089]

[0090] Formula (I)

[0091] wherein:

[0092] ring A is a 4- to 7-membered cycloalkyl or a 4- to 7-membered heterocycloalkyl;

[0093] R4 is each independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2R a, -N=S(=O)(Rb)2, -C(=O)R a, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R4a;

[0094] Or two R4 atoms on the same atom together form an oxo group;

[0095] Or two R4 atoms on the same atom together form a cycloalkyl or heterocycloalkyl group; each of which is optionally substituted by one or more R4b;

[0096] R4a are each independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)R a, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0097] or two R4a on the same atom together form an oxo group;

[0098] R4b are each independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SR a, ‑S(=O)Ra, ‑S(=O)2R a, ‑S(=O)2NR cRd, ‑S(=O)(=NRb)Rb, ‑NRcRd, ‑NRbC(= Instructions 10 / 206 Page 21 CN 121285551 AO)NRcRd,‑NRbC(=O)Ra,‑NRbC(=O)ORb,‑NRbS(=O)2R a,‑N=S(=O)(Rb)2,‑C(=O)R a,‑C(=O)ORb,‑C (=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0099] or two R4b on the same atom together form an oxo group;

[0100] n is 1, 2, 3, 4, 5 or 6;

[0101] R5 is -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R5a;

[0102] R5a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O) NRcRd, ‑SF5, ‑SH, ‑SR a,‑S(=O)Ra,‑S(=O)2R a,‑S(=O)2NR cRd,‑S(=O)(=NRb)Rb,‑NRcRd,‑NRbC(= O)NRcRd,‑NRbC(=O)Ra,‑NRbC(=O)ORb,‑NRbS(=O)2R a,‑N=S(=O)(Rb)2,‑C(=O)R a,‑C(=O)ORb,‑C (=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0103] or two R5a on the same atom together form an oxo group;

[0104] W is N or CRW;

[0105] RW is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 olefin-L-alkyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0106] U is N or CRU;

[0107] RU is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2R a, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0108] T is N or CRT;

[0109] RT is hydrogen, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, - SH,‑SRa,‑S(=O)Ra,‑S(=O)2R a,‑S(=O)2NR cRd,‑S(=O)(=NRb)Rb,‑NRcRd,‑NRbC(=O)NRcRd,‑NRbC (=O)Ra,‑NRbC(=O)ORb,‑NRbS(=O)2R a,‑N=S(=O)(Rb)2,‑C(=O)R a,‑C(=O)ORb,‑C(=O)NRcRd,‑P (=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0110] X is C and Y is C; Specification 11 / 206 pages 22 CN 121285551 A

[0111] or X is C and Y is N;

[0112] or X is N and Y is C;

[0113] Z1 is O, S, N, NR1a, CR1b, or C(R1c)2;

[0114] Z2 is O, S, N, NR2a, CR2b, or C(R2c)2;

[0115] Z3 is O, S, N, NR3a, CR3b, or C(R3c)2;

[0116] R1a, R2a, and R3a are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R;

[0117] R1b, R2b, and R3b are each independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R;

[0118] R1c is each independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0119] or two R1c together form an oxo group;

[0120] R2c is each independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0121] or two R2c together form an oxo group;

[0122] R3c are each independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl,C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently and optionally substituted by one or more Rs;

[0123] or two Rs together form an oxo group;

[0124] Ra is each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0125] Rb is each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heteroalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heteroalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R;

[0126] Rc and Rd are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heteroalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heteroalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R;

[0127] or Rc and Rd together with the atoms to which they are attached form a heteroalkyl group, which is optionally substituted by one or more R;

[0128] L is absent or is a C1-C4 alkylene group optionally substituted with one or more R; and specification 12 / 206 page 23 CN 121285551 A

[0129] R is each independently a halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl)2, -O-C1-C4 alkylene-OH, -O-C1-C4 alkylenealkyl-NH2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl or 3 to 6-membered heterocyclic alkyl;

[0130] or two R on the same atom form an oxo group.

[0131] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salts or stereoisomers, R4 is each independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(=O) (Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R4a.

[0132] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salts or stereoisomers, R4 is each independently a halogen, -ORa, C1-C6 alkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R4a.

[0133] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, R4 is each independently -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently and optionally substituted by one or more R4a.

[0134] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, R4 is independently -L-aryl, wherein the aryl group is independently and optionally substituted by one or more R4a.

[0135] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt or stereoisomer, R4 is independently -L-heteroaryl; wherein the heteroaryl group is independently and optionally substituted by one or more R4a.

[0136] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, R4 is each independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -SF5, -SH, -SRa, -NRcRd, -NRbC(=O)Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R4a.

[0137] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, two R4s on the same atom together form an oxo group.

[0138] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salts or stereoisomers, two R4 atoms on the same atom together form a cycloalkyl or heterocycloalkyl group; each is optionally substituted by one or more R4b. In some embodiments, two R4 atoms on the same atom together form a cycloalkyl or heterocycloalkyl group; each is optionally and independently substituted. In some embodiments, two R4 atoms on the same atom together form a cycloalkyl group; each is optionally substituted by one or more R4b. In some embodiments, two R4 atoms on the same atom together form a fully saturated cycloalkyl group; each is optionally substituted by one or more R4b. In some embodiments, two R4 atoms on the same atom together form a partially saturated cycloalkyl group; each is optionally substituted by one or more R4b. In some embodiments, two R4 atoms on the same atom together form a 4- to 6-membered fully saturated cycloalkyl group; each is optionally substituted by one or more R4b. In some embodiments, two R4 atoms on the same atom (page 13 / 206, 24 CN 121285551 A) together form a 4- to 6-membered partially saturated cycloalkyl group; optionally substituted by one or more R4b. In some embodiments, two R4 atoms on the same atom together form a heterocyclic alkyl group; optionally substituted by one or more R4b. In some embodiments, two R4 atoms on the same atom together form a fully saturated heterocyclic alkyl group; optionally substituted by one or more R4b. In some embodiments, two R4 atoms on the same atom together form a partially saturated heterocyclic alkyl group; optionally substituted by one or more R4b. In some embodiments, two R4 atoms on the same atom together form a 4- to 6-membered fully saturated heterocyclic alkane.The compound is optionally substituted with one or more R4b. In some embodiments, two R4 atoms on the same atom together form a 4- to 6-membered partially saturated heterocyclic alkyl group; which is optionally substituted with one or more R4b.

[0139] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, two R4 atoms on the same atom together form a 5- to 6-membered cycloalkyl group or a 5- to 6-membered heterocyclic alkyl group; each is optionally substituted with one or more R4b.

[0140] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, two R4 atoms on the same atom together form a 5-membered cycloalkyl group; each is optionally substituted with one or more R4b.

[0141] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, two R4 atoms on the same atom together form a 6-membered cycloalkyl group; each is optionally substituted with one or more R4b.

[0142] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, two R4 atoms on the same atom together form a 5-membered heterocyclic alkyl group; each is optionally substituted by one or more R4b.

[0143] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, two R4 atoms on the same atom together form a 6-membered heterocyclic alkyl group; each is optionally substituted by one or more R4b.

[0144] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, two R4 atoms on the same atom together form a cycloalkyl or heterocyclic alkyl group; each is optionally substituted by one or more R4b, wherein the cycloalkyl or heterocyclic alkyl group is fused with an aryl or heteroaryl group. In some embodiments, two R4 atoms on the same atom together form a cycloalkyl group; each is optionally substituted by one or more R4b, wherein the cycloalkyl group is fused with an aryl or heteroaryl group. In some embodiments, two R4 atoms on the same atom together form a heterocyclic alkyl group; each is optionally substituted by one or more R4b, wherein the heterocyclic alkyl group is fused with an aryl or heteroaryl group.

[0145] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt or stereoisomer, R4a is each independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted. In some embodiments, R4a is each independently a halogen, -CN, -OH, -ORa, -SF5, -S(=O)2Ra, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted by one or more R. In some embodiments, R4a are each independently a halogen, -CN, -OH, -ORa, -SF5, -S(=O)2Ra, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is optionally independently substituted by one or more Rs.

[0146] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salts or stereoisomers, the two R4a on the same atom together form an oxo group. Instructions for Use, 14 / 206 pages, 25 CN 121285551 A

[0147] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt or stereoisomer, R4b is each independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)R a、-C(=O)ORb、-C(=O)NRcRd、-P(=O) (Rb)2、C1-C6 alkyl、C1-C6 haloalkyl、C1-C6 hydroxyalkyl、C1-C6 aminoalkyl、C1-C6 heteroalkyl、C2-C6 alkenyl、C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted.

[0148] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salts or stereoisomers, R4b is each independently a halogen, -CN, -NO2, -OH, -ORa, -SF5, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R. In some embodiments, R4b are each independently a halogen, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is optionally independently substituted by one or more R.

[0149] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, the two R4b on the same atom together form an oxo group.

[0150] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, n is 1, 2, 3, 4, 5, or 6. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 0.

[0151] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salts or stereoisomers, the compound has formula (Ia):

[0152]

[0153] Formula (Ia)

[0154] wherein:

[0155] Ring B is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0156] R6 are each independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(= O)NRcRd,‑NRbC(=O)Ra,‑NRbC(=O)ORb,‑NRbS(=O)2R a,‑N=S(=O)(Rb)2,‑C(=O)R a,‑C(=O)ORb,‑C(=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0157] or two R6s on the same atom together form an oxo group;

[0158] m is 0, 1, 2, 3, 4, 5 or 6;

[0159] R7s are each independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O) (Specification 15 / 206 pages 26 CN) 121285551 A NRcRd,‑SF5,‑SH,‑SR a,‑S(=O)Ra,‑S(=O)2R a,‑S(=O)2NRcRd,‑S(=O)(=NRb)Rb,‑NRcRd,‑NRbC(= O)NRcRd,‑NRbC(=O)Ra,‑NRbC(=O)ORb,‑NRbS(=O)2R a,‑N=S(=O)(Rb)2,‑C(=O)R a,‑C(=O)ORb,‑C (=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0160] or two R7s on the same atom together form an oxo group;

[0161] p is 0, 1, 2, 3, 4 or 5; and

[0162] L1 is absent or is a C1-C4 alkylene group optionally substituted by one or more Rs.

[0163] This document describes compounds of formula (Ia) or pharmaceutically acceptable salts or stereoisomers thereof:

[0164]

[0165] Formula (Ia)

[0166] wherein:

[0167] ring B is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0168] R6 is each independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0169] or two R6s on the same atom together form an oxo group;

[0170] m is 0, 1, 2, 3, 4, 5 or 6;

[0171] R7 is independently a halogen, -CN, -NO2, -OH, -ORα, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRα, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C (=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0172] or two R7s on the same atom together form an oxo group;

[0173] p is 0, 1, 2, 3, 4 or 5;

[0174] L1 is absent, is -NRc- or C1-C4 alkylene, wherein the C1-C4 alkylene is optionally substituted by one or more R;

[0175] Ring A is a 4- to 7-membered cycloalkyl or a 4- to 7-membered heterocycloalkyl;

[0176] R5 represents -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, and C2-C6 olefin.-L-alkyl, -L-cycloalkyl, -L-heteroalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl and heteroaryl group is independently and optionally substituted by one or more R5a;

[0177] R5a is each independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(= O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0178] or two R5a on the same atom together form an oxo group;

[0179] W is N or CRW; RW is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)Ra, -S(=O)NR cRd,‑S(=O)(=NRb)Rb,‑NRcRd,‑NRbC(=O)NRcRd,‑NRbC (=O)Ra,‑NRbC(=O)ORb,‑NRbS(=O)2R a,‑N=S(=O)(Rb)2,‑C(=O)R a,‑C(=O)ORb,‑C(=O)NRcRd,‑P (=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0181] U is N or CRU;

[0182] RU is hydrogen, halogen, -CN, -NO2, -OH, -ORa,‑OC(=O)Ra,‑OC(=O)ORb,‑OC(=O)NRcRd,‑SF5,‑SH,‑SRa,‑S(=O)Ra,‑S(=O)2R a,‑S(=O)2NR cRd,‑S(=O)(=NRb)Rb,‑NRcRd,‑NRbC(=O)NRcRd,‑NRbC (=O)Ra,‑NRbC(=O)ORb,‑NRbS(=O)2R a,‑N=S(=O)(Rb)2,‑C(=O)R a,‑C(=O)ORb,‑C(=O)NRcRd,‑P (=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0183] T is N or CRT;

[0184] RT is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NR cRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0185] X is C, and Y is C;

[0186] or X is C, and Y is N;

[0187] or X is N, and Y is C;

[0188] Z1 is O, S, N, NR1a, CR1b, or C(R1c)2;

[0189] Z2 is O, S, N, NR2a, CR2b, or C(R2c)2;

[0190] Z3 is O, S, N, NR3a, CR3b, or C(R3c)2;

[0191] R1a, R2a, and R3a are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 amino.Alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R; Specification 17 / 206 pages 28 CN 121285551 A

[0192] R1b, R2b and R3b are each independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, - L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R;

[0193] R1c is each independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R;

[0194] or two R1c together form an oxo group;

[0195] R2c are each independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R;

[0196] or two R2c together form an oxo group;

[0197] R3c are each independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is optionally substituted by one or more R groups independently;

[0198] Or two R3c together form an oxo group;

[0199] Ra is each independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R;

[0200] Rb is each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heteroalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heteroalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R;

[0201] Rc and Rd are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heteroalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heteroalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R;

[0202] or Rc and Rd together with the atoms to which they are attached form a heteroalkyl group, which is optionally substituted by one or more R;

[0203] L is absent or optionally substituted with one or more Rs, and

[0204] R is each independently a halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), - NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl)2, -O-C1-C4 alkylene-OH, -O-C1-C4 alkylene-NH2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl or 3 to 6-membered heterocyclic alkyl;

[0205] Or, two R atoms on the same atom can form an oxo group.

[0206] In some embodiments of the compound of formula (Ia) or a pharmaceutically acceptable salt or stereoisomer thereof, L1 is absent. Specification 18 / 206 pages 29 CN 121285551 A

[0207] In some embodiments of the compound of formula (Ia) or a pharmaceutically acceptable salt or stereoisomer thereof, L1 is a C1-C4 alkylene group optionally substituted with one or more R groups. In some embodiments, L1 is -CH2-.

[0208] In some embodiments of the compound of formula (Ia) or a pharmaceutically acceptable salt or stereoisomer thereof, L1 is -NRc-. In some embodiments, L1 is -NH-.

[0209] In some embodiments of the compounds of formula (Ia) or (Ib) or their pharmaceutically acceptable salts or stereoisomers, R6 is each independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)Ra, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, - L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is optionally substituted by one or more R groups independently.

[0210] In some embodiments of the compound of formula (Ia) or (Ib) or its pharmaceutically acceptable salt or stereoisomer, R6 is each independently a halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -NRcRd, -C(=O)Ra, -C(=O)ORb, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R.

[0211] In some embodiments of compounds of formula (Ia) or (Ib) or their pharmaceutically acceptable salts or stereoisomers, R6 is each independently a halogen, -CN, -NO2, -OH, -ORa, -SF5, S(=O)2Ra, -NRcRd, C1-C6 alkyl, C1-C6 haloalkane.The compounds are C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, and heteroaryl; wherein each alkyl, alkynyl, cycloalkyl, heterocycloalkyl, and heteroaryl is independently and optionally substituted by one or more R.

[0212] In some embodiments of the compounds of formula (Ia) or (Ib) or their pharmaceutically acceptable salts or stereoisomers, R6 is each independently a halogen, -CN, -NO2, -OH, -ORa, -SF5, S(=O)2Ra, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkynyl, cycloalkyl, or heterocycloalkyl is independently and optionally substituted by one or more R. In some embodiments, one or more R6 are halogens. In some embodiments, one or more R6 are -CN. In some embodiments, one or more R6s are -NO2. In some embodiments, one or more R6s are OH. In some embodiments, one or more R6s are S(=O)2Ra. In some embodiments, one or more R6s are NRcRd. In some embodiments, one or more R6s are optionally substituted C1-C6 alkyl groups. In some embodiments, one or more R6s are optionally substituted C1-C3 alkyl groups. In some embodiments, one or more R6s are optionally substituted C1-C6 alkoxy groups, optionally substituted with one or more halogens. In some embodiments, one or more R6s are optionally substituted C1-C3 alkoxy groups. In some embodiments, one or more R6s are C1-C6 haloalkyl groups. In some embodiments, one or more R6s are optionally substituted C2-C6 alkynyl groups. In some embodiments, one or more R6s are optionally substituted cycloalkyl groups. In some embodiments, one or more R6s are optionally substituted 3- to 6-membered cycloalkyl groups. In some embodiments, one or more R6s are optionally substituted heterocyclic alkyl groups. In some embodiments, one or more R6s are optionally substituted 3- to 6-membered heterocyclic alkyl groups. In some embodiments, one or more R6s are optionally substituted heteroaryl groups. In some embodiments, one or more R6s are CN, F, Cl, CH3, CH2CH3, CH(CH3)2, CHF2, CF3, OCH2F, OCF3, or CN 121285551 A. In some embodiments, two R6s on the same atom together form an oxo group.

[0213] In some embodiments of compounds of formula (Ia) or pharmaceutically acceptable salts or stereoisomers thereof, ring B is a cycloalkyl or heterocycloalkyl group. In some embodiments, ring B is a fully saturated cycloalkyl group. In some embodiments, ring B is a fully saturated cycloalkyl group.B is a fully saturated heterocyclic alkyl group. In some embodiments, ring B is a partially saturated cycloalkyl group. In some embodiments, ring B is a partially saturated heterocyclic alkyl group. In some embodiments, ring B is a partially saturated 5- to 6-membered heterocyclic alkyl group. In some embodiments, ring B is a bridged bicyclic ring. In some embodiments, ring B is a spirobicyclic ring. In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, ring B is a 4- to 7-membered ring. In some embodiments, ring B is a bicyclic ring. In some embodiments, ring B is a monocyclic ring.

[0214] In some embodiments of the compound of formula (Ia) or a pharmaceutically acceptable salt or stereoisomer thereof, ring B is an aryl group. In some embodiments, the aryl group comprises a phenyl group fused with a cycloalkyl or heterocyclic alkyl group. In some embodiments, is , or . In some embodiments, is .

[0215] In some embodiments of the compound of formula (Ia) or a pharmaceutically acceptable salt or stereoisomer thereof, ring B is a phenyl group. In some embodiments, is 20 / 206 pages 31 CN 121285551 A or .

[0216] In some embodiments of the compound of formula (Ia) or its pharmaceutically acceptable salt or stereoisomer, is or .

[0217] In some embodiments of the compound of formula (Ia) or its pharmaceutically acceptable salt or stereoisomer, is . In some embodiments, is . In some embodiments of the compound of formula (Ia) or its pharmaceutically acceptable salt or stereoisomer, is . In some embodiments, is .

[0218] In some embodiments of the compound of formula (Ia) or its pharmaceutically acceptable salt or stereoisomer, is . In some embodiments, is . 21 / 206 pages 32 CN 121285551 A In some embodiments, is .

[0219] In some embodiments of the compound of formula (Ia) or its pharmaceutically acceptable salt or stereoisomer, ring B is a heteroaryl group. In some embodiments, ring B is a bicyclic heteroaryl. In some embodiments, ring B is a 5-6, 6-6, or 6-5 fused bicyclic heteroaryl. In some embodiments, it is or.

[0220] In some embodiments of the compound of formula (Ia) or its pharmaceutically acceptable salt or stereoisomer, ring B is a monocyclic heteroaryl. In some embodiments, ring B is a 5- to 6-membered heteroaryl. In some embodiments, ring B is a 5-membered heteroaryl. In some embodiments, ring B is a pyrazolyl, pyrroleyl, or thiazolyl. In some embodiments, ring B is a 6-membered heteroaryl. In some embodiments, ring B is a pyridinyl, pyrimidinyl, or pyridazinyl.

[0221] In some embodiments of the compound of formula (Ia) or its pharmaceutically acceptable salts or stereoisomers, is or .

[0222] In some embodiments of the compound of formula (Ia) or its pharmaceutically acceptable salts or stereoisomers, is or . (See specification 22 / 206, page 33, CN 121285551 A).

[0223] In some embodiments of the compound of formula (Ia) or its pharmaceutically acceptable salts or stereoisomers, is or .

[0224] In some embodiments of the compound of formula (Ia) or its pharmaceutically acceptable salts or stereoisomers, is . (See specification 23 / 206, page 34, CN 121285551 A).

[0225] In some embodiments of the compound of formula (Ia) or (Ib) or its pharmaceutically acceptable salts or stereoisomers, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some implementations, m is 4. In some implementations, m is 5. In some implementations, m is 0, 1, 2, or 3. In some implementations, m is 2, 3, 4, or 5. In some implementations, m is 3, 4, or 5. In some implementations, m is 4 or 5.

[0226] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salts or stereoisomers, the compound has formula (Ib):

[0227]

[0228] Formula (Ib)

[0229] wherein:

[0230] the ring C is a cycloalkyl or heterocycloalkyl;

[0231] R6 are each independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2R a、-N=S(=O)(Rb)2、-C(=O)R a、-C(=O)ORb、-C (=O)NRcRd、-P(=O)(Rb)2、C1-C6 alkyl、C1-C6 haloalkyl、C1-C6 hydroxyalkyl、C1-C6 aminoalkyl、C1-C6 heteroalkyl、C2-C6 alkenyl、C2-C6 alkynyl、-L-cycloalkyl、-L-heterocycloalkyl、-L-aryl or -L-heteroaryl; wherein each alkyl、alkenyl、alkynyl、cycloalkyl、heterocycloalkyl、aryl and heteroaryl is independently and optionally substituted by one or more R;

[0232] Or two R6 atoms on the same atom together form an oxo group;

[0233] m is 0, 1, 2, 3, 4, 5 or 6;

[0234] R7 is independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C (=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more Rs;

[0235] or two R7s on the same atom together form an oxo group;

[0236] q is 0, 1, 2, 3 or 4.

[0237] In some embodiments of the compounds of formula (Ia) or (Ib) or their pharmaceutically acceptable salts or stereoisomers, R6 is each a halogen or -L-heteroaryl; wherein the heteroaryl is independently and optionally substituted by one or more Rs. In some embodiments, one or more R6s are halogens. In some embodiments, one or more R6 are -L-heteroaryl; wherein the heteroaryl is optionally substituted independently by one or more R.

[0238] In some embodiments of the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt or stereoisomer thereof, two R6 on the same atom together form an oxo group.

[0239] In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt or stereoisomer thereof, ring C is a 4- to 6-membered cycloalkyl or a 4- to 6-membered heterocycloalkyl. In some embodiments, ring C is a bicyclic. In some embodiments, ring C is a monocyclic.

[0240] In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt or stereoisomer thereof, ring C is a 4- to 6-membered fully saturated cycloalkyl. In some embodiments, ring C is a 4- to 6-membered partially saturated cycloalkyl. In some embodiments, ring C is a partially saturated ring containing a double bond.

[0241] In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt or stereoisomer thereof, is or .

[0242] In some embodiments of the compound of formula (Ib) or its pharmaceutically acceptable salts or stereoisomers, is or .

[0243] In some embodiments of the compound of formula (Ib) or its pharmaceutically acceptable salts or stereoisomers, ring C is a cycloalkyl group comprising a fused aryl or heteroaryl group. In some embodiments, is . Specification 25 / 206 pages 36 CN 121285551 A

[0244] In some embodiments of the compound of formula (Ib) or its pharmaceutically acceptable salts or stereoisomers, ring C is a 4- to 6-membered fully saturated heterocyclic alkyl group. In some embodiments, is or . In some embodiments, is or .

[0245] In some embodiments of the compound of formula (Ib) or its pharmaceutically acceptable salts or stereoisomers, ring C is a heterocyclic alkyl group comprising a fused aryl or heteroaryl group. In some embodiments, is .

[0246] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salts or stereoisomers, is . In some embodiments, is.

[0247] In some embodiments of compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, ring A is a 4- to 6-membered cycloalkyl. In some embodiments, ring A is a 4- to 6-membered fully saturated cycloalkyl. In some embodiments, ring A is a 4-membered fully saturated cycloalkyl. In some embodiments, ring A is a 5-membered fully saturated cycloalkyl. In some embodiments, ring A is a 6-membered fully saturated cycloalkyl. In some embodiments, ring A is a 4- to 6-membered partially saturated cycloalkyl. In some embodiments, ring A is a 4- to 6-membered partially saturated cycloalkyl containing a double bond. In some embodiments, ring A is a 5-membered partially saturated cycloalkyl. In some embodiments, ring A is a 6-membered partially saturated cycloalkyl. In some embodiments, ring A contains a double bond on the ring.

[0248] In some embodiments of compounds of formula (I), (Ia), or (Ib) or pharmaceutically acceptable salts or stereoisomers thereof, as described on page 26 / 206 of CN 121285551 A, ring A is or. In some embodiments, ring A is. In some embodiments, ring A is. In some embodiments, ring A is.

[0249] In some embodiments of compounds of formula (I) or pharmaceutically acceptable salts or stereoisomers thereof, is or or. In some embodiments, is. In some embodiments, is.

[0250] In some embodiments of compounds of formula (I), (Ia), or (Ib) or pharmaceutically acceptable salts or stereoisomers thereof, ring A is a 4- to 7-membered heterocyclic alkyl group. In some embodiments, ring A is a 4- to 6-membered heterocyclic alkyl group. In some embodimentsIn this embodiment, ring A comprises 1-3 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms. In some embodiments, ring A comprises 1-3 cyclic nitrogen atoms. In some embodiments, ring A comprises 1-2 cyclic nitrogen atoms. In some embodiments, ring A comprises 1 cyclic nitrogen atom. In some embodiments, ring A is a 4- to 6-membered fully saturated heterocyclic alkyl group. In some embodiments, ring A is a 4-membered fully saturated heterocyclic alkyl group. In some embodiments, ring A is a 5-membered fully saturated heterocyclic alkyl group. In some embodiments, ring A is a 6-membered fully saturated heterocyclic alkyl group. In some embodiments, ring A is a 4- to 6-membered partially saturated heterocyclic alkyl group. In some embodiments, ring A is a 4- to 6-membered partially saturated heterocyclic alkyl group containing a double bond. In some embodiments, ring A is a 5-membered partially saturated heterocyclic alkyl group. In some embodiments, ring A is a 6-membered partially saturated heterocyclic alkyl group.

[0251] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, ring A is or .

[0252] In some embodiments of the compounds of formula (I) or their pharmaceutically acceptable salts or stereoisomers, is or .

[0253] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, as described in the specification 27 / 206 pages 38 CN 121285551 A, ring A is a 4- to 6-membered partially saturated heterocyclic alkyl group.

[0254] In some embodiments of the compounds of formula (Ia) or their pharmaceutically acceptable salts or stereoisomers, is or .

[0255] In some embodiments of the compounds of formula (Ia) or their pharmaceutically acceptable salts or stereoisomers, is or .

[0256] In some embodiments of the compound of formula (Ib) or its pharmaceutically acceptable salt or stereoisomer, it is _____ or _____.

[0257] In some embodiments of the compound of formula (Ib) or its pharmaceutically acceptable salt or stereoisomer, it is _____ or _____.

[0258] In some embodiments of the compounds of formula (Ia) or (Ib) or their pharmaceutically acceptable salts or stereoisomers, R7 is each independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)R, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R. Specification 29 / 206 pages 40 CN 121285551 A

[0259] In some embodiments of the compound of formula (Ia) or (Ib) or its pharmaceutically acceptable salt or stereoisomer, R7 is each independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -SF5, -SH, -SRa, -NRcRd, -NRbC(=O)Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R.

[0260] In some embodiments of compounds of formula (Ia) or (Ib) or their pharmaceutically acceptable salts or stereoisomers, R7 is each independently a halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, R7 is each independently a halogen, -OH, -ORa, amino, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R7 is each independently a halogen, -OH, C1-C6 alkoxy, C1-C6 alkyl, or C1-C6 haloalkyl, wherein the alkoxy group is optionally substituted with one or more halogens. In some embodiments, R7 is each independently a halogen, C1-C6 alkoxy, or C1-C6 alkyl, wherein the alkoxy group is optionally substituted with one or more halogens.

[0261] In some embodiments of compounds of formula (Ia) or (Ib) or pharmaceutically acceptable salts or stereoisomers thereof, the two R7s on the same atom together form an oxo group.

[0262] In some embodiments of compounds of formula (I), (Ia) or (Ib) or pharmaceutically acceptable salts or stereoisomers thereofIn this embodiment, R5 is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally substituted by one or more R5a. In some embodiments, R5 is a C1-C6 alkyl, optionally substituted by one or more R5a. In some embodiments, R5 is a C1-C6 haloalkyl. In some embodiments, R5 is a C1-C6 hydroxyalkyl. In some embodiments, R5 is a C1-C6 aminoalkyl. In some embodiments, R5 is a C1-C6 heteroalkyl. In some embodiments, R5 is a C2-C6 alkenyl, optionally substituted by one or more R5a. In some embodiments, R5 is a C2-C6 alkynyl group, which is optionally substituted with one or more R5a. In some embodiments, R5 is an L-cycloalkyl group, wherein the cycloalkyl group is optionally substituted with one or more R5a. In some embodiments, R5 is an -L-heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with one or more R5a. In some embodiments, R5 is an -L-aryl group, wherein the aryl group is optionally substituted with one or more R5a. In some embodiments, R5 is an -L-heteroaryl group, wherein the heteroaryl group is optionally substituted with one or more R5a.

[0263] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, R5 is a C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl group, wherein the alkyl group is optionally substituted with one or more R5a.

[0264] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, R5 is a methyl group.

[0265] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, R5 is ethyl.

[0266] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, R5 is -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R5a. In some embodiments, R5 is -L-(3 to 6-membered cycloalkyl), -L-(3 to 6-membered heterocycloalkyl), -L-phenyl, or -L-(5 to 6-membered heteroaryl), wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R5a.

[0267] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, R5 is ethyl.Page 30 / 206, 41 CN 121285551 A. In the scheme, L is absent or is -CH2-. In some embodiments, L is absent. In some embodiments, L is -CH2-. In some embodiments, L is a C1-C4 alkylene group optionally substituted with one or more Rs.

[0268] In some embodiments of compounds of formula (I), (Ia) or (Ib) or their pharmaceutically acceptable salts or stereoisomers, R5 is or.

[0269] In some embodiments of the compounds of formula (I), (Ia) or (Ib) or their pharmaceutically acceptable salts or stereoisomers, R5a is each independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -NRcRd, -NRbC(=O)Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; wherein the alkyl group is independently optionally substituted by one or more R.

[0270] In some embodiments of the compounds of formula (I), (Ia) or (Ib) or their pharmaceutically acceptable salts or stereoisomers, R5a is each independently a halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; wherein the alkyl group is independently and optionally substituted by one or more Rs.

[0271] In some embodiments of the compounds of formula (I), (Ia) or (Ib) or their pharmaceutically acceptable salts or stereoisomers, R5 is CH3, CHF2, CF3, CH2CH3, CH2CH(CH3)2, CH2CHF2, CH2CF3, or.

[0272] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, W is N.

[0273] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, W is CRW.

[0274] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, as described in specification 31 / 206 pages 42 CN 121285551 A, RW is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; wherein the alkyl group is optionally substituted with one or more R. In some embodiments, RW is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, RW is C1-C6 alkyl. In some embodiments, RW is hydrogen. In some embodiments, RW is halogen.

[0275] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, U is N.

[0276] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, U is CRU.

[0277] In some embodiments of the compounds of formula (I), (Ia) or (Ib) or their pharmaceutically acceptable salts or stereoisomers, RU is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally independently substituted by one or more R.

[0278] In some embodiments of compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, RU is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; wherein the alkyl group is optionally substituted with one or more R. In some embodiments, RU is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, RU is C1-C6 alkyl. In some embodiments, RU is hydrogen. In some embodiments, RU is halogen. In some embodiments, RU is C1-C6 alkyl.

[0279] In some embodiments of the compounds of formula (I), (Ia), or (Ib), or pharmaceutically acceptable salts or stereoisomers thereof, T is N.

[0280] In some embodiments of the compounds of formula (I), (Ia), or (Ib), or pharmaceutically acceptable salts or stereoisomers thereof, T is CRT.

[0281] In some embodiments of the compounds of formula (I), (Ia), or (Ib), or pharmaceutically acceptable salts or stereoisomers thereof, T is CRT.In this scheme, RT is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently and optionally substituted by one or more R. In some embodiments, RT is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, RT is C1-C6 alkyl.

[0282] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, RT is hydrogen, halogen, -CN, -NO2, -OH, -NR cRd, -C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0283] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, RT is hydrogen, halogen, -C1-C3 alkyl, C1-C3 haloalkyl, or C2-C3 alkynyl. In some embodiments, RT is hydrogen. In some embodiments, RT is halogen. In some embodiments, RT is -C1-C3 alkyl. In some embodiments, RT is C1-C3 haloalkyl. In some embodiments, RT is C2-C3 alkynyl.

[0284] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, RT is hydrogen. Specification 32 / 206 pages 43 CN 121285551 A

[0285] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, X is C and Y is C. In some embodiments, X is C and Y is N. In some embodiments, X is N and Y is C.

[0286] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, Z1 is O. In some embodiments, Z1 is S. In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, Z1 is N. In some embodiments, Z1 is NR1a. In some embodiments, Z1 is CR1b. In some implementations, Z1 is C(R1c)2.

[0287] In some embodiments of compounds of formula (I), (Ia), or (Ib) or pharmaceutically acceptable salts or stereoisomers thereof, Z2 is O. In some embodiments, or stereoisomers thereof, Z2 is S. In some embodiments, Z2 is N. In some embodiments, Z2 is NR2a. In some embodiments, Z2 is CR2b. In some embodiments, Z2 is or C(R2c)2.

[0288] In some embodiments of compounds of formula (I), (Ia), or (Ib) or pharmaceutically acceptable salts or stereoisomers thereof, Z3 is O. In some embodiments, Z3 is S. In some embodiments, Z3 is N. In some embodiments, Z3 is NR3a. In some embodiments, Z3 is CR3b. In some embodiments, Z3 is C(R3c)2.

[0289] In some embodiments of compounds of formula (I), (Ia), or (Ib) or pharmaceutically acceptable salts or stereoisomers thereof, is .

[0290] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, is .

[0291] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, is .

[0292] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, is .

[0293] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, R1a, R2a, and R3a are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, R1a is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, R2a is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, R3a is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0294] In some embodiments of compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, R1a, R2a, and R3a are each independently hydrogen or C1-C3 alkyl (e.g., methyl). In some implementations, R1a independentlyR2a is hydrogen or a C1-C3 alkyl (e.g., methyl). In some embodiments, R2a is independently hydrogen or a C1-C3 alkyl (e.g., methyl). In some embodiments, R3a is independently hydrogen or a C1-C3 alkyl (e.g., methyl). In some embodiments, R1a is hydrogen. In some embodiments, R1a is methyl. In some embodiments, R2a is hydrogen. In some embodiments, R2a is methyl. In some embodiments, R3a is hydrogen. In some embodiments, R3a is methyl.

[0295] In some embodiments of compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, R1b, R2b, and R3b are each independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, R1b is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, R2b is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, R3b is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0296] In some embodiments of compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, R1b, R2b, and R3b are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R1b is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R1b is hydrogen. In some embodiments, R1b is C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments, R2b is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R2b is hydrogen. In some embodiments, R2b is a C1-C6 alkyl or a C1-C6 haloalkyl. In some embodiments, R3b is independently hydrogen, a C1-C6 alkyl, or a C1-C6 haloalkyl. In some embodiments, R3b is hydrogen.In some embodiments, R3b is a C1-C6 alkyl or C1-C6 haloalkyl.

[0297] In some embodiments of compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, R1b, R2b, and R3b are each independently hydrogen or C1-C3 alkyl (e.g., methyl). In some embodiments, R1b is independently hydrogen or C1-C3 alkyl (e.g., methyl). In some embodiments, R1b is methyl. In some embodiments, R2b is independently hydrogen or C1-C3 alkyl (e.g., methyl). In some embodiments, R2b is methyl. In some embodiments, R3b is independently hydrogen or C1-C3 alkyl (e.g., methyl). In some embodiments, R3b is methyl.

[0298] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, R1c is each independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, R1c is each independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R1c is each independently hydrogen.

[0299] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, the two R1cs together form an oxo group.

[0300] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, R2c is each independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, R2c is each independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0301] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, as described in the specification 34 / 206 pages 45 CN 121285551 A, R2c is each independently hydrogen.

[0302] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, the two R2cs together form an oxo group.

[0303] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, each R3c is independently hydrogen, halogen, -CN, -NO2, -OH, -OR.a, -SF5, -SH, -SR a, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, each R3c is independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0304] In some embodiments of compounds of formula (I), (Ia), or (Ib) or pharmaceutically acceptable salts or stereoisomers thereof, each R3c is independently hydrogen.

[0305] In some embodiments of compounds of formula (I), (Ia), or (Ib) or pharmaceutically acceptable salts or stereoisomers thereof, the two R3cs together form an oxo group.

[0306] In some embodiments of compounds of formula (I), (Ia), or (Ib) or pharmaceutically acceptable salts or stereoisomers thereof, is . In some embodiments, is or .

[0307] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, is .

[0308] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, is .

[0309] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, is .

[0310] In some embodiments of the compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts or stereoisomers, is . In some embodiments, is or . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is .

[0311] In some embodiments of the compounds of formula (I), (Ia) or (Ib) or their pharmaceutically acceptable salts or stereoisomers, as described on page 36 / 206 of CN 121285551 A, is . In some embodiments, is or .

[0312] In some embodiments of the compounds of formula (I), (Ia) or (Ib) or their pharmaceutically acceptable salts or stereoisomers, is . In some embodiments, is or .

[0313] In some embodiments of the compounds disclosed herein, Ra is each independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R.In some embodiments of the compounds disclosed herein, Ra is each independently -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, Ra is each independently -L-cycloalkyl or -L-heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, Ra is each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, wherein each alkyl group is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, Ra is each independently C1-C6 alkyl or C1-C6 haloalkyl, wherein each alkyl group is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, Ra is each independently a C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, Ra is each independently a C1-C6 alkyl. In some embodiments of the compounds disclosed herein, Ra is each independently a C1-C6 haloalkyl.

[0314] In some embodiments of the compounds disclosed herein, Rb is each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R. In some embodiments of the compounds disclosed herein, Rb is each independently hydrogen, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, Rb is each independently hydrogen, -L-cycloalkyl, or -L-heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, Rb is each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, wherein each alkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, Rb is each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl, wherein each alkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, Rb is each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl, wherein each alkyl is independently and optionally substituted with one or more R.Hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, Rb is each independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, Rb is each independently hydrogen or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, Rb is each hydrogen. In some embodiments of the compounds disclosed herein, Rb is each independently C1-C6 alkyl. In some embodiments of the compounds disclosed herein, Rb is each independently C1-C6 haloalkyl.

[0315] In some embodiments of the compounds disclosed herein, Rc and Rd are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted by one or more R. In some embodiments of the compounds disclosed herein, Rc and Rd are each independently hydrogen, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted by one or more R. In some embodiments of the compounds disclosed herein, Rc and Rd are each independently hydrogen, -L-cycloalkyl, or -L-heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted by one or more R. In some embodiments of the compounds disclosed herein, Rc and Rd are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, wherein each alkyl is independently optionally substituted by one or more R.

[0316] In some embodiments of the compounds disclosed herein, Rc and Rd are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl, wherein each alkyl is independently optionally substituted by one or more R. In some embodiments of the compounds disclosed herein, Rc and Rd are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, Rc and Rd are each independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, Rc and Rd are each independently hydrogen or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, Rc and Rd are each hydrogen. In some embodiments of the compounds disclosed herein, Rc and Rd are each independently C1-C6 alkyl. In some embodiments of the compounds disclosed herein, Rc and Rd are each independently C1-C6 haloalkyl.

[0317] In some embodiments of the compounds disclosed herein, Rc and Rd together with the atoms to which they are attached form a heteroCycloalkyl, optionally substituted with one or more R; and

[0318] In some embodiments of the compounds disclosed herein, L is absent. In some embodiments of the compounds disclosed herein, L is a C1-C3 alkylene group optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, L is a C1-C3 alkylene group. In some embodiments of the compounds disclosed herein, L is -CH2-. In some embodiments of the compounds disclosed herein (page 38 / 206, CN 121285551 A), L is -CH2CH2-. In some embodiments of the compounds disclosed herein, L is -CH2CH2CH2-.

[0319] In some embodiments of the compounds disclosed herein, R is each independently a halogen, -CN, -OH, -SF5, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl. In some embodiments of the compounds disclosed herein, R is each independently a halogen, -CN, -OH, -SF5, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl. In some embodiments of the compounds disclosed herein, R is each independently a halogen, -CN, -OH, -SF5, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments of the compounds disclosed herein, R is each independently a halogen, -CN, -OH, -SF5, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl. In some embodiments of the compounds disclosed herein, R is independently a halogen, -CN, -OH, -SF5, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 haloalkyl. In some embodiments of the compounds disclosed herein, R is each independently a halogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0320] Any combination of groups of the various variables described above is considered herein. Throughout the specification, those skilled in the art select groups and their substituents to provide stable moieties and compounds.

[0321] In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts or stereoisomers, are one of the compounds in Table 1.

[0322] Table 1. Exemplary Compounds

[0323] Specification 39 / 206 pages 50 CN 121285551 A Specification 40 / 206 pages 51 CN 121285551 A Specification 41 / 206 pages 52 CN 121285551 A Specification 42 / 206 pages 53 CN 121285551 A Specification 43 / 206 pages 54 CN 121285551 A Specification 44 / 206 pages 55 CN 121285551 A Specification 45 / 206 pages 56 CN 121285551 A Specification 46 / 206 pages 57 CN 121285551 A Specification 47 / 206 pages 58 CN 121285551 A Specification 48 / 206 pages 59 CN 121285551 A Specification 49 / 206 pages 60 CN 121285551 A Specification 50 / 206 pages 61 CN 121285551 A Specification 51 / 206 pages 62 CN 121285551 A

[0324] In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts or stereoisomers are one of the compounds in Table 2.

[0325] Table 2

[0326] Specification 52 / 206 pages 63 CN 121285551 A

[0327] Specification 53 / 206 pages 64 CN 121285551 A

[0328] Specification 54 / 206 pages 65 CN 121285551 A

[0329]

[0330] Other forms of the compounds disclosed herein

[0331] Isomers / stereoisomers

[0332] In some embodiments, the compounds described herein are present as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds described herein include all cis (cis, syn,The compounds described herein include diastereomers (Z), trans (anti, engegen (E)) isomers, and mixtures thereof. In some embodiments, the compounds described herein have one or more chiral centers, each present in an R or S configuration. The compounds described herein include all diastereomers, enantiomers, and epimers, and mixtures thereof. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers produced by a single preparation step, combination, or interconversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared as separate stereoisomers by reacting a racemic mixture of compounds with an optically active resolving agent to form a pair of diastereomer compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.), and these differences are utilized for separation. In some embodiments, diastereomers are separated by chiral chromatography, or preferably by a separation / resolution technique based on differences in solubility. In some embodiments, the optically pure enantiomers and the resolving agent are subsequently recovered by any practical method that does not result in racemization.

[0333] Isotope-enriched compounds

[0334] Unless otherwise stated, the compounds described herein may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched with a specific isotope having the same atomic number but a different atomic mass or mass number than that predominantly found in nature. All isotopic variants of the compounds disclosed herein, whether radioactive or not, are covered within the scope of this disclosure. For example, hydrogen has three naturally occurring isotopes, denoted as 1H (protium), 2H (deuterium), and 3H (tritium). Protium is the most abundant hydrogen isotope in nature. Enrichment of deuterium may provide some therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide compounds for studying in vivo drug elimination and metabolic pathways.

[0335] For example, the compounds described herein can be artificially enriched with one or more specific isotopes. In some embodiments, the compounds described herein can be artificially enriched with one or more isotopes that are not predominantly found in nature. In some embodiments, the compounds described herein can be artificially enriched with one or more isotopes selected from deuterium (2H), tritium (3H), iodine-125 (125I), or carbon-14 (14C). In some embodiments, the compounds described herein are artificially enriched with one or more isotopes selected from...2H, 11C, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 16O, 17O, 14F, 15F, 16F, 17F, 18F, 33S, 34S, 35S, 36S, 35Cl, 37Cl, 79Br, 81Br, 131I, and 125I. In some embodiments, the abundance of enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% on a molar basis.

[0336] In some embodiments, the compound is deuterated at at least one position. In some embodiments, some or all of the 1H atoms of the compounds disclosed herein are replaced by 2H atoms.

[0337] Methods for synthesizing deuterium-containing compounds are known in the art, and non-limiting examples include the methods described in U.S. Patent Specification 55 / 206, page 66, CN 121285551 A, Nos. 5,846,514 and 6,334,997, as well as the following synthetic methods. For example, deuterium-substituted compounds can be synthesized using various methods, such as those described in the following literature: Dean, Dennis C.; editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0338] Pharmaceutically Acceptable Salts

[0339] In some embodiments, the compounds described herein are present in the form of their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts in the form of a pharmaceutical composition.

[0340] In some embodiments, the compounds described herein have acidic or basic groups and are therefore reactable with a variety of inorganic or organic bases and any of inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final separation and purification of the compounds disclosed herein, or by additionally reacting the purified compound in its free form with a suitable acid or base and separating the resulting salt.

[0341] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with inorganic acids, organic acids, or inorganic bases, including acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, bisulfites, bromides, butyrates, butyn-1,4-dicitates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, digluconate, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucono-heptyl salts, glycerophosphates, glycolates, hemisulfates, heptasulfates, heptasulfates, hexyn-1,6-dicitates, and hydroxybenzoates. Hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, pyrosulfate, pyrophosphate, propynate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, octanoate, sebacic acid salt, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0342] Further, the compounds described herein can be prepared into pharmaceutically acceptable salts by reacting the compounds in their free base form with pharmaceutically acceptable inorganic or organic acids, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2] Oct-2-en-1-carboxylic acid, glucoheponic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecyl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucoconic acid. In some embodiments, other acids (e.g., oxalic acid), although not pharmaceutically acceptable on their own, may be used to prepare salts that can be used as intermediates to obtain the compounds disclosed herein and their pharmaceutically acceptable acid addition salts. Specification 56 / 206 pages 67 CN 121285551 A

[0343] In some embodiments, those compounds comprising free acid groups described herein react with suitable bases, such as hydroxides, carbonates, bicarbonates, sulfates of pharmaceutically acceptable metal cations, with ammonia, or with pharmaceutically acceptable primary, secondary, tertiary, or quaternary organic amines. Representative salts include alkali or alkaline earth metal salts, such as lithium, sodium, potassium, calcium and magnesium salts, and aluminum salts. Exemplary examples of alkalis include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, etc.

[0344] Representative organic amines that can be used to form alkali addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. It should be understood that the compounds described herein also include quaternary ammonium compounds containing any basic nitrogen-containing groups. In some embodiments, such quaternization yields water- or oil-soluble or dispersible products.

[0345] Tautomers

[0346] In some cases, compounds exist in the form of tautomers. The compounds described herein include all possible tautomers of the structures described herein. Tautomers are compounds that can be interconverted by hydrogen atom migration, accompanied by the conversion of single bonds and adjacent double bonds. In the bond arrangements in which tautomerization may occur, there will be a chemical equilibrium of tautomers. All tautomer forms of the compounds disclosed herein are considered. The exact proportions of the tautomers depend on a variety of factors, including temperature, solvent, and pH.

[0347] Treatment Methods

[0348] Methods for treating cancer are disclosed herein, comprising administering to an individual the compounds described herein or pharmaceutically acceptable salts thereof.

[0349] In some embodiments, the method for treating cancer comprises administering to an individual an effective amount of the compounds described herein or pharmaceutically acceptable salts thereof.

[0350] Methods for inhibiting PRMT5 activity in an individual are also disclosed herein, comprising administering to an individual the compounds described herein or pharmaceutically acceptable salts thereof.

[0351] Methods for regulating protein arginine methyltransferase 5 (PRMT5) in an individual in need are disclosed herein, comprising administering to an individual the compounds described herein or pharmaceutically acceptable salts thereof.

[0352] This document discloses a method for inhibiting protein arginine methyltransferase 5 (PRMT5) in an individual in need, the method comprising administering to the individual a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the individual has cancer.

[0353] This document discloses a method for treating a disease or condition, the method comprising administering to an individual in need a compound described herein or a pharmaceutically acceptable salt thereof, wherein the disease or condition is associated with overexpression of PRMT5. In some embodiments, the disease or condition is cancer.

[0354] This document discloses a method for treating cancer, the method comprising administering to an individual in need a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is selected from pancreatic cancer, colorectal cancer, uterine cancer, bile duct cancer, gastric cancer, bladder cancer, cervical cancer, testicular germ cell cancer, non-small cell lung cancer and multiple myeloma, diffuse large B-cell lymphoma, rhabdomyosarcoma and squamous cell carcinoma of the skin. In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is malignant mesothelioma.

[0355] In some embodiments, the compounds disclosed herein, described herein, or pharmaceutically acceptable salts thereof are effective in inhibiting the cell proliferation of cancer cells, including cancer cells lacking the MTAP gene.

[0356] In some embodiments, the cancer is a cancer in which the MTAP gene is lacking.

[0357] In some embodiments, the cancer is MTAP (methionine phosphorylase)-free. In some embodiments, the cancer exhibits accumulation of the MTAP substrate methionine (MTA). Specification 57 / 206 pages 68 CN 121285551 A

[0358] In some embodiments, these methods target PRMT5 in MTAP-deficient tumors while omitting PRMT5 in normal tissue (MTAP WT). In some embodiments, the compounds disclosed herein are MTA-synergistic small molecule inhibitors that preferentially target the MTA-binding state of PRMT5 enriched in MTAP-deficient tumor cells while providing an improved therapeutic index relative to normal cells (where MTAP is intact and MTA levels are low).

[0359] In some embodiments, the cancer is mesothelioma, breast cancer, multiple myeloma, leukemia, lymphoma, glioblastoma, lung cancer, liver cancer, colorectal cancer, melanoma, ovarian cancer, kidney cancer, pancreatic cancer, gastric cancer, cervical cancer, esophageal cancer, nasopharyngeal cancer, laryngeal cancer, skin cancer, prostate cancer, breast cancer, or gastrointestinal cancer.

[0360] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is estrogen receptor-negative (ER-) or progesterone receptor-negative (PR-).

[0361] In some embodiments, the breast cancer is HER2-negative. In some embodiments, the breast cancer is estrogen receptor-negative.Negative, progesterone receptor negative, and HER2 negative, also referred to in this article as "triple-negative breast cancer".

[0362] In some embodiments, the breast cancer is lobular carcinoma in situ (LCIS), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC), inflammatory breast cancer, Paget's disease of the nipple, phyllodes tumor, angiosarcoma, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary breast carcinoma, mixed carcinoma, or another type of breast cancer, including but not limited to triple-negative, HER2-positive, estrogen receptor-positive, progesterone receptor-positive, HER2 and estrogen receptor-positive, HER2 ... And progesterone receptor positive, estrogen and progesterone receptor positive, and HER and estrogen and progesterone receptor positive.

[0363] In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is NSCLC (non-small cell lung cancer). In some embodiments, NSCLC is squamous NSCLC. In some embodiments, it is adenocarcinoma. In some embodiments, the cancer is glioblastoma (GBM). In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is DLBCL, HNSCC, or cholangiocarcinoma.

[0364] In some embodiments, the cancer includes, but is not limited to, acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, hemangiosarcoma), appendiceal cancer, benign monoclonal gammopathy, biliary tract cancer. Cancers such as bile duct cancer, bladder cancer, brain cancer (e.g., meningioma; glioma, such as astrocytoma, oligodendroglioma; medulloblastoma), bronchial cancer, carcinoid tumors, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, and chordoma.(chordoma), craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial cancer, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing sarcoma, ocular cancer (e.g., intraocular melanoma, retinoblastoma), familiar hypereosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma (OSCC), throat cancer (e.g., laryngeal cancer, pharyngeal cancer)). Cancer, nasopharyngeal carcinoma or oropharyngeal carcinoma, hematopoietic system cancers (e.g., leukemia, such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML) and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodular marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma. Lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (e.g., Waldenström macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL, such as precursor T lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma).Lymphoma), subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma; a mixture of one or more of the above-mentioned leukemias / lymphomas; and multiple myeloma (MM), heavy chain disease (e.g., chain disease, chain disease, chain disease), hemangioblastoma, inflammatory myofibroblastoma, immune cell amyloidosis, renal cell carcinoma (e.g., nephroblastoma, also known as Wilms' tumor), hepatocellular carcinoma (e.g., hepatocellular carcinoma (HCC), malignant hepatocellular carcinoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma), leiomyosarcoma (LMS), mastocytosis (e.g., generalized mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disease (MPD) (e.g., polycythemia vera), PV), essential thrombocythemia (ET), agnogenic myeloid metaplasia (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), eosinophilic syndrome (HES), neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis), neuroendocrine carcinoma (e.g., gastrointestinal pancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, penile cancer (e.g., Paget's disease of the penis and scrotum), pineal tumor, primitive neuroectodermal tumor, PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCO), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma), malignantPeripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma, sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicular cancer (e.g., seminoma, embryonal testis), thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid (PTC), medullary thyroid carcinoma), urethral cancer, vaginal cancer, and vulvar cancer (e.g., vulvar Paget's disease).

[0365] In some embodiments, the disclosed compounds are used to treat any PRMT5-mediated or PRMT5-responsive proliferative cell disease, such as cancers that respond to PRMT5.

[0366] Administration

[0367] In some embodiments, a composition comprising the compounds described herein is administered for therapeutic treatment. In some therapeutic applications, the composition is administered to a patient who already has a disease or condition, in an amount sufficient to cure or at least partially suppress at least one symptom of the disease or condition. The effective amount used for this purpose depends on the severity and course of the disease or condition, prior therapy, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician. Instructions for Use 59 / 206 pages 70 CN 121285551 A

[0368] Routes of Administration

[0369] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ear, nasal, and topical administration. Furthermore, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, and intrathecal, direct intracardiac, intraperitoneal, intralymphatic, and intranasal injection.

[0370] Pharmaceutical Compositions / Formulations

[0371] The compounds described herein are administered, alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, as pharmaceutical compositions to individuals in need, in accordance with standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0372] In another aspect, this document provides pharmaceutical compositions comprising the compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically acceptable formulation. A suitable formulation depends on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in the following literature: Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference.

[0373] Examples

[0374] The following examples are provided to illustrate the claimed invention, but do not limit the claimed invention. The following examples further illustrate the invention, but should not be construed as limiting its scope in any way.

[0375] The following synthetic schemes are provided for illustration and not limitation. The following examples illustrate various methods for preparing the compounds described herein. It should be understood that those skilled in the art can prepare these compounds by similar methods or by combining other methods known to those skilled in the art. It should also be understood that those skilled in the art can prepare the materials in a manner similar to that described below by using appropriate raw materials and modifying the synthetic route as needed. Generally, the raw materials and reagents may be obtained from commercial suppliers, synthesized from sources known to those skilled in the art, or prepared as described herein.

[0376] Examples

[0377] Unless otherwise recorded, all materials were obtained from commercial suppliers and used without further purification.

[0378] The following abbreviations are used to refer to different reagents and solvents: Specification 60 / 206 page 71 CN 121285551 A

[0379] Specification 61 / 206 page 72 CN 121285551 A

[0380] Specification 62 / 206 page 73 CN 121285551 A

[0381]

[0382] Example A

[0383] Intermediate A01

[0384]

[0385] 2-methyl-1H-imidazole (44.5 g, 542 mmol) and K2CO3 (125 g, 904 mmol) were added to a solution of A01-01 (90.0 g, 452 mmol) in CH3CN (800 mL). The reaction was stirred at 85 °C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated. Dilute the residue with H2O (1.00 L) and extract with DCM (800 mL x 3). Dry with anhydrous Na2SO4.The combined organic layers were filtered and concentrated under reduced pressure to give A01-02 (87.8 g, 74.4% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.29 (dd, J=8.4, 1.6 Hz, 1H), 8.09 (d, J=1.6 Hz, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.06 (d, J=1.2 Hz, 1H), 6.91 (d, J=1.2 Hz, 1H), 3.99 (s, 3H), 2.22 (s, 3H).

[0386] Fe (32.0 g, 574 mmol) and CaCl2 (21.2 g, 191 mmol) were added to a solution of A01-02 (50.0 g, 191 mmol) in EtOH (500 mL) and H2O (250 mL). The reaction was stirred at 70 °C for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was diluted with H2O (500 mL) and extracted with DCM (500 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give A01-03 (40 g, 90.3% yield). 1H NMR (400MHz, DMSO‑d 6) δ 7.74 (dd , J=8.4 , 2.0 Hz, 1H) , 7.49 (d , J=2.0 Hz, 1H) , 7.08 (d , J=1.2 Hz, 1H) , 6.94 (d , J=1.2 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 5.85 (s, 2H), 3.75 (s, 3H), 2.08 (s, 3H).

[0387] CDI (61.7 g, 380 mmol) was added to a solution of A01-03 (40.0 g, 173 mmol) in 1,2-dichlorobenzene (400 mL). The reaction was stirred at 180 °C for 4 hours. After cooling to 20 °C, the reaction was filtered, and the solid was washed with THF (100 mL). The solid was dried under vacuum to give A01-04 (40 g, 89.9% yield). LCMS: MS m / z (ESI) [M+H]+=258.1.

[0388] BOP (138 g, 311 mmol) and DBU (71.0 g, 467 mmol) were added to a solution of A01-04 (40.0 g, 155 mmol) in CH3CN (400 mL). The mixture at 25The mixture was stirred at ℃ for 30 minutes, after which (2,4-dimethoxyphenyl)methylamine (39.0 g, 233 mmol) was added. The resulting mixture was stirred at 50 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was diluted with H2O (2 L), and extracted with DCM (1 L x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 100 / 0-2 / 3) to give A01-05 (23.0 g, 36.4% yield). LCMS: MS m / z (ESI) [M+H]+ = 406.9.

[0389] The mixture of A01-05 (23.0 g, 56.6 mmol) in TFA (150 mL) was stirred at 80 ℃ for 2 hours and then concentrated. The residue was ground together with the solution (petroleum ether / EtOAc = 1 / 1, 200 ml) at 25 °C for 2 hours, filtered, and the solid was dried under vacuum to give A01-06 (14.0 g, 96.5% yield). LCMS: MS m / z (ESI) [M+H]+=257.3.

[0390] LiOH (13.1 g, 546 mmol) was added to a solution of A01-06 (14.0 g, 54.6 mmol) in THF (150 mL) and H2O (100 mL). The mixture was stirred at 70 °C for 2 hours. After cooling to room temperature, the reaction mixture was adjusted to pH=3 with 3 M HCl (100 mL). The mixture was then filtered, the solid was washed with THF (80 mL), and dried under vacuum to give A01 (13.2 g, 99.8% yield). LCMS: MS m / z (ESI) [M+1]+=243.1; 1H NMR (400MHz, DMSO‑ d6) δ 10.12 (brs, 1H) , 9.53 (brs, 1H) , 8.64 (s, 1H) , 8.55 (s, 1H) , 8.06 (d, J =8.4 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 3.08 (s, 3H).

[0391] Intermediate A02

[0392]

[0393] Methyl glycine hydrochloride (37.9 g, 301 mmol) and DIPEA (58.4 g, 452 mmol) were added to a solution of A02-01 (15 g, 75.3 mmol) in CH3CN (150 mL). The reaction mixture was stirred at 80 °C for 4 hours. The reaction mixture was concentrated under vacuum. The residue (SiO2, petroleum ether / THF 0 to 20%) was purified by silica gel chromatography to give A02-02 (5.3 g, 75.3 mmol).g, 26.2% yield). 1H NMR (400MHz, CDCl3) δ 8.38 (brs, 1H), 8.27 (d, J=8.8 Hz, 1H), 7.41 (d, J=1.6 Hz, 1H), 7.34 (dd, J=8.8, 1.6 Hz, 1H), 4.18 (d, J=5.2 Hz, 2H), 3.96 (s, 3H), 3.86 (s, 3H).

[0394] Fe (4.20 g, 74.6 mmol) and CaCl2 (2.10 g, 18.6 mmol) were added to a solution of A02-O2 (5.00 g, 18.6 mmol) in EtOH (50 mL) and H2O (10 mL). The reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated to give A02-03 (3.00 g, 78.1% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (See specification 64 / 206 pages, CN 121285551) ¹H NMR (400 MHz, DMSO-d₆) δ ¹⁰.58 (s, ¹H), ¹⁰.28 (s, ¹H), ¹⁰.23 (dd, J=8.0, 1.6 Hz, ¹H), ¹⁰.79 (d, J=8.0 Hz, ¹H), ¹⁰.25 (s, ¹H), ¹⁰.38 (s, ³H).

[0395] MnO2 (5.10 g, 58.2 mmol) was added to a solution of A02-03 (3.00 g, 14.5 mmol) in THF (30 mL). The reaction was stirred at 25 °C for 12 hours. The reaction mixture was filtered, and the filter cake was washed with warm THF (30 mL). The filtrate was concentrated to give A02-04 (1.60 g, 53.9% yield). ¹H NMR (400MHz, DMSO-d₆) δ 12.71 (brs, ¹H), 8.28 (d, J=2.0 Hz, ¹H), 8.25 (s, ¹H), 8.09 (dd, J=8.4, 2.0 Hz, ¹H), 7.38 (d, J=8.4 Hz, ¹H), 3.88 (s, ³H).

[0396] A₂-O₄ (500 mg, 2.45 mmol) was added to a suspension of NaH (196 mg, 4.90 mmol, 60% purity) in DMF (5 mL) at 0 °C under N₂ atmosphere. The reaction was stirred at 0 °C for 30 minutes, then PMB-Cl (499 mg, 3.18 mmol) was added, and the mixture was stirred for another 12 hours. NH4Cl (20...) was then used...The reaction solution was quenched with 20 mL of EtOAc (3 x 3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by silica gel chromatography (SiO2, petroleum ether / THF, 0 to 30%) to give A02-05 (420 mg, 52.9% yield). LCMS: MS m / z (ESI) [M+H]+=325.2. 1H NMR (400MHz, DMSO‑d 6) δ 8.44 (s, 1H) , 8.34 (d , J=2.0 Hz, 1H) , 8.09 (dd, J=8.8, 2.0 Hz, 1H) , 7.65 (d, J=8.8 Hz, 1H), 7.26 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 5.44 (s, 2H), 3.89 (s, 3H), 3.72 (s, 3H).

[0397] NaH (123.3 mg, 3.08 mmol) and TosMIC (482 mg, 2.47 mmol) were added to a solution of A02-05 (400 mg, 1.23 mmol) in DMF (10 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 12 hours. The reaction mixture was quenched with H2O (40 mL), and HCl (2 M) was added until pH = 3-4. The mixture was then extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, PE / THF = 0 to 50%) to give A02-06 (210 mg, 46.9% yield). LCMS: MS m / z (ESI) [M+H]+=350.3.

[0398] K2CO3 (166 mg, 1.20 mmol) and CH3I (171 mg, 1.20 mmol) were added to a solution of A02-06 (210 mg, 0.601 mmol) in DMF (5 mL). The reaction was stirred at 25 °C for 2 hours. The reaction solution was diluted with H2O (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (SiO2, PE / THF=0 to 33%) to give A02-07 (200 mg, 91.5% yield). LCMS: MS m / z (ESI) [M+H]+=364.3.

[0399] To A02-07 (270 mg, 0.74TfOH (0.300 mL, 0.200 mmol) was added to a solution of A02-08 (100 mg, 0.410 mmol) in CH3CN (3 mL). The reaction was stirred at 25 °C for 3 hours. The reaction mixture was concentrated and the crude product (SiO2, DCM / MeOH = 100 / 0-20 / 1) was purified by column chromatography to give A02-08 (130 mg, 80.6% yield). LCMS: MS m / z (ESI) [M+H]+=244.1.

[0400] To a solution of A02-08 (100 mg, 0.410 mmol) in CH3CN (3 mL), (2,4-dimethoxyphenyl)methylamine (103 mg, 0.620 mmol), BOP (364 mg, 0.820 mmol) and DBU (188 mg, 1.23 mmol) were added. The reaction mixture was stirred at 50 °C for 12 hours. The reaction mixture was concentrated under reduced pressure, the residue was diluted with H₂O (10 mL), and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, DCM / MeOH = 100 / 0-20 / 1) to give A₂-09 (130 mg, 80.6% yield). LCMS: MS m / z (ESI) [M+H]+=393.3; 1H NMR (400MHz, CDCl3) δ 8.61 (s, 1H) , 8.45 (d , J=2.0 Hz, 1H) , 8.05 (dd , J=8.4, 2.0 Hz, 1H) , 7.70 (d , , 4.83 (d , J=4.8 Hz, 2H), 3.98 (s, 3H), 3.88 (s, 3H), 3.81 (s, 3H). Specification 65 / 206 pages 76 CN 121285551 A

[0401] A solution of A02-09 (130 mg, 0.330 mmol) in TFA (3 mL) was stirred at 80 °C for 2 hours. The reaction mixture was concentrated, and the residue was ground together with the solution (10 mL, PE: EtOAc = 1:1), filtered, and the solid was dried under vacuum to give A02-10 (65.0 mg, 81.0% yield). LCMS: MSm / z (ESI) [M+H]+=243.2.

[0402] LiOH (47.7 mg, 1.14 mmol) was added to a solution of A02-10 (55.0 mg, 0.230 mmol) in THF (3 mL) and H2O (1 mL). The mixture was stirred at 70 °C for 12 hours. After cooling to room temperature, the reaction mixture was adjusted to pH=3 with 3 M HCl. The mixture was filtered, the solid was washed with THF (1 mL), and dried under vacuum to give A02 (36.0 mg, 69.5% yield). LCMS: MS m / z (ESI) [M+H]+=229.1.

[0403] Intermediate A03

[0404]

[0405] Cs2CO3 (11.8 g, 36.1 mmol) and Pd(PPh3)4 (2.1 g, 1.80 mmol) were added to a solution of A03-01 (5.00 g, 18.0 mmol) and 5-bromo-1H-imidazole (3.20 g, 21.7 mmol) in dioxane (80 mL) and H2O (8 mL). The mixture was stirred at 100 °C under N2 atmosphere for 12 hours. The reaction was filtered, and the filtrate was removed under vacuum to obtain the residue. The residue was diluted with saturated H2O (200 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (0 to 20% THF / DCM eluent 100 mL / min) to give A03-02 (500 mg, 12.8% yield). LCMS: MS m / z (ESI) [M+H]+= 218.0; 1H NMR (400 MHz, DMSO-d6) δ 12.39 (brs, 1H), 8.04 (d, J=2.0 Hz, 1H), 7.80 (s, 1H), 7.61 (s, 1H), 7.54 (dd, J=8.4, 2.0 Hz, 1H), 7.17 (s, 2H), 6.71 (d, J=8.4 Hz, 1H), 3.77 (s, 3H).

[0406] CDI (747 mg, 4.60 mmol) was added to a mixture of A03-02 (500 mg, 2.30 mmol) in THF (10 mL), and the mixture was stirred at 70 °C for 12 hours. The reaction was filtered, and the filter cake was concentrated under reduced pressure to give A03-03 (200 mg, 35.7% yield). LCMS: MS m / z (ESI) [M+H]+=243.9; 1HNMR (400 MHz, DMSO-d6) δ 12.00 (brs, 1H), 8.54 (d, J=1.6 Hz, 1H), 8.53 (s, 1H), 8.02 (s, 1H), 7.96 (dd, J=8.4, 2.0 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 3.88 (s, 3H).

[0407] DIPEA (0.76 mL, 4.56 mmol) was added to a mixture of A03-O3 (370 mg, 1.52 mmol) and POCl3 (4 mL, 43.1 mmol), and the mixture was stirred at 90 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by rapid silica gel chromatography (0 to 6% THF / DCM gradient elution @ 50 mL / min) to give A03-04 (80 mg, 20.1% yield). LCMS: MS m / z (ESI) [M+H]+=262.0.

[0408] TEA (95.4 μL, 0.688 mmol) was added to a mixture of A03-04 (76.7 mg, 0.459 mmol) in THF (2 mL), and the mixture was stirred at 60 °C for 2 h. The reaction was concentrated to give the residue. The residue was ground together with DCM (2 mL) at 25 °C for 1 h, filtered, and dried under vacuum to give A03-05 (70 mg, 77.8% yield). LCMS: MS m / z (ESI) [M+H]+=393.3.

[0409] The mixture of A03-05 (60 mg, 0.153 mmol) in TFA (1 mL, 0.153 mmol) was stirred at 80 °C for 2 hours. The reaction was concentrated under vacuum to obtain the residue. The residue was diluted with THF (1 mL), and then the pH was adjusted to >7 with saturated NaHCO3, and then filtered. The solid was dried under vacuum to obtain A03-06 (30 mg, 81.0% yield). LCMS: MS m / z (ESI) [M +H]+=243.0.

[0410] LiOH H2O (2.89 mL, 2.89 mmol) was added to a mixture of A03-06 (30 mg, 0.124 mmol) in THF (0.5 mL), and the mixture was stirred at 50 °C for 5 hours. The pH of the reaction mixture was adjusted to 4 with 1 M HCl, and then filtered. The solid was dried under vacuum to give A03 (30 mg, crude product). LCMS: MS m / z (ESI)[M+H]+=228.9.

[0411] Intermediate A04

[0412]

[0413] The title compound was prepared from methyl 2,5-difluoro-4-nitrobenzene (A04-01) using a method similar to that described for the synthesis of A01. LCMS: MS m / z (ESI) [M+H]+=261.1.

[0414] Intermediate A05

[0415]

[0416] K2CO3 (24.4 g, 177 mmol) and 2-methyl-1H-imidazole (5.80 g, 70.8 mmol) were added to a solution of A05-01 (15.0 g, 59.0 mmol) in CH3CN (150 mL). The reaction was stirred at 85 °C for 2 h. The reaction mixture was concentrated to remove CH3CN, diluted with H2O (500 mL), and extracted with DCM (300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give A05-02 (18.0 g, 96.5% yield). LCMS: MS m / z (ESI) [M+H]+=315.9; 1H NMR (400MHz, CDCl3) δ 8.18 (s, 1H), 7.74 (s, 1H), 7.05 (d, J=1.2 Hz, 1H), 6.88 (d, J=1.2 Hz, 1H), 2.23 (s, 3H).

[0417] To a solution of A05-02 (17.0 g, 53.7 mmol) in EtOH (180 mL) and H2O (90 mL), CaCl2 (6.00 g, 53.7 mmol) and Fe (9.0 g, 161 mmol) were added. The reaction was stirred at 75 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to remove EtOH. The resulting mixture was diluted with H2O (300 mL) and extracted with DCM (200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give crude product A05-03 (14.0 g, 90.9% yield). LCMS: MS m / z (ESI) [M+H]+=285.8; 1H NMR (400MHz, DMSO‑ d 6) δ 7.39 (s, 1H) , 7.08 (s , 1H) , 7.07 (s, 1H) , 6.93 (s, 1H) , 5.42 (s , 2H) , 2.11 (s, 3H).

[0418] To A05-03 (13.6CDI (16.9 g, 104 mmol) was added to a solution of 1,2-dichlorobenzene (150 mL). The reaction was stirred at 180 °C for 4 hours. The reaction was cooled to 30 °C and filtered. The filter cake was washed with THF (100 mL) and dried under vacuum to give A05-04 (14.4 g, 97.1% yield). LCMS: MS m / z (ESI) [M+H]+ = 311.8; 1H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 8.22 (s, 1H), 7.77 (s, 1H), 7.49 (s, 1H), 2.93 (s, 3H).

[0419] BOP (35.1 g, 79.3 mmol) and DBU (18.1 g, 119 mmol) were added to a solution of A05-04 (12.4 g, 39.7 mmol) in CH3CN (200 mL). The mixture was stirred at 25 °C for 0.5 h, and then (2,4-dimethoxyphenyl)methylamine (9.90 g, 59.5 mmol) was added. The mixture was stirred at 50 °C for 15.5 h. The reaction mixture was concentrated to remove CH3CN, and the residue was dissolved in DCM (300 mL) and filtered. The filtrate was washed with H2O (500 mL) and extracted with DCM (200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by rapid silica gel chromatography (330 g silica gel rapid column, elution gradient of 0 to 60% THF / petroleum ether @ 100 mL / min) to give A05-05 (15.7 g, 85.7% yield). LCMS: MS m / z (ESI) [M+H]+=460.7; 1H NMR (400MHz, CDCl3) δ 8.16 (s, 1H), 7.77 (s, 1H), 7.43 (s, 1H), 7.33 (d, J=8.0 Hz, 1H), 6.49 (d, J=2.0 Hz, 1H) , 6.46 (dd, J=8.4, 2.4 Hz, 1H) , 5.56 (t, J=5.2 Hz, 1H) , 4.75 (d, J=5.6 Hz, 2H) , 3.87 (s, 3H) , 3.80 (s, 3H), 2.98 (s, 3H).

[0420] Pd(dppf)Cl2 was added to a solution of A05-05 (2.00 g, 4.33 mmol) in MeOH (30 mL).(317 mg, 0.433 mmol) and sodium methoxide (4.01 mL, 21.6 mmol). The mixture was stirred at 80 °C for 16 hours under CO (50 psi). The reaction solution was filtered. The filter cake was washed with EtOAc (10 mL 2) and dried under vacuum to give A05-06 (1.80 g, 47.1% yield). LCMS: MS m / z (ESI) [M+H]+=441.1.

[0421] The solution of A05-06 (1.50 g, 3.40 mmol) in TFA (20 mL) was stirred at 80 °C for 2 hours. The reaction was concentrated under vacuum to remove TFA and ground together with EtOAc (10 mL) at 25 °C for 20 minutes. The mixture was filtered and dried under vacuum to give A05-07 (1.30 g, 47.2% yield). LCMS: MS m / z (ESI) [M+H]+=291.0.

[0422] LiOH (780 mg, 18.6 mmol) was added to a mixture of A05-07 (900 mg, 3.10 mmol) in THF (8 mL) and H2O (4 mL). The reaction was stirred at 80 °C for 16 hours. The reaction was concentrated to remove THF. The resulting mixture was adjusted to pH 3-4 with 1M HCl and then filtered. The filter cake was washed with THF (10 mL) and dried under vacuum to give A05 (600 mg, 70.0% yield). LCMS: MS m / z (ESI) [M+H]+=276.8.

[0423] Intermediate A06 Specification 68 / 206 pages 79 CN 121285551 A

[0424]

[0425] To a solution of A06-01 (10.0 g, 44.5 mmol) in DCE (200 mL), m-CPBA (27.1 g, 134 mmol) was added. The reaction was stirred at 70 °C for 16 hours. The reaction mixture was diluted with DCM (100 mL), washed with water (50 mL), and then washed with saturated Na2SO3 aqueous solution (200 mL). The organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (petroleum ether solution of 0 to 6% ethyl acetate) by dissolving the compound in MTBE (50 mL) and stirring for 10 minutes. The solution was then filtered, and the filtrate was concentrated under reduced pressure to obtain A06-02 (7.0 g, 61.8% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.53 (t, J = 2.0 Hz, ¹H), 7.30 (dd, J = 8.8, 2.0 Hz, ¹H).

[0426] A06 was prepared from A06-02 using a method similar to that used for the synthesis of A05. LCMS: MS m / z (ESI) [M+H]+=277.0.

[0427] Intermediate A07

[0428]

[0429] A03-01 (9.40 g, 33.9 mmol), Xphos (2.30 g, 4.84 mmol), XPhos Pd G3 (2.00 g, 2.42 mmol), and K3PO4 (15.4 g, 72.6 mmol) were added to a solution of 5-bromo-1-methyl-1H-pyrazole-4-carboxynitrile (4.50 g, 24.2 mmol) in dioxane (100 mL) and H2O (20 mL). The reaction was stirred at 80 °C under a N2 atmosphere for 12 hours. The reaction mixture was concentrated. The residue was ground together with EtOAc / H2O (100 ml / 50 ml) at 25 °C for 2 hours, filtered, and the solid was dried under vacuum to give A07-01 (6.08 g, 71.6% yield). LCMS: MS m / z (ESI) [M+H]+= 257.3.

[0430] LiOH (9.80 g, 234 mmol) was added to a solution of A07-01 (6.00 g, 23.4 mmol) in THF (60 mL) and H2O (60 mL). The reaction was stirred at 80 °C for 16 hours. After cooling to room temperature, the reaction mixture was adjusted to pH=5 with 3 M HCl. The mixture was filtered, the solid was washed with THF (10 mL), and dried under vacuum to give A07 (5.60 g, 97.4% yield). LCMS: MS m / z (ESI) [M+H]+=243.0. Specification 69 / 206 pages 80 CN 121285551 A

[0431] Intermediate A08

[0432]

[0433] DIPEA (0.940 mL, 5.45 mmol) was added to a solution of A08-01 (500 mg, 4.50 mmol) in DCM (5 mL), and the reaction mixture was cooled to -78 °C. Then Tf2O (0.760 mL, 4.50 mmol) was added dropwise at -78 °C, and the reaction mixture was stirred at the same temperature for 15 minutes. After completion, the reaction mixture was quenched with water (5 mL), extracted with DCM (10 mL 2), the combined organic layers were washed with brine (10 mL), dried with sodium sulfate, filtered, and concentrated to give A08-02 (1.00 g, 91.4% yield). ¹H NMR (400 MHz, CDCl₃) δ 4.94–4.80 (m, 4H).

[0434] To A08-02 (1.00 g 2), the reaction mixture was quenched with water (5 mL), extracted with DCM (10 mL 2), washed with brine (10 mL 2), dried with sodium sulfate, filtered, and concentrated to give A08-02 (1.00 g, 91.4% yield).K₂CO₃ (920 mg, 6.66 mmol) and Pd(PPh₃)₄ (256 mg, 0.222 mmol) were added to a solution of dioxane (20 mL) and H₂O (2 mL). The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated, and the residue was diluted with EtOAc (20 mL) and water (20 mL). The mixture was stirred at 25 °C for 30 min and then filtered. The solid was washed with EtOAc (10 mL) and dried under vacuum to give A₀₈-03 (128 mg, 23.6% yield). LCMS: MS m / z (ESI) [M+H]+=245.3.

[0435] Lithium hydroxide (50.1 mg, 2.10 mmol) was added to a mixture of A08-03 (128 mg, 0.524 mmol) in THF (1 mL) and H2O (1 mL). The mixture was stirred at 75 °C for 3 hours. The reaction mixture was concentrated, and the residue was acidified to pH 6.0 with 1.5 M HCl. The mixture was filtered, the solid was washed with methanol (5 mL), and dried under vacuum to give A08 (83 mg, 68.8% yield). LCMS: MS m / z (ESI) [M+H]+=231.3.

[0436] Intermediate A09

[0437]

[0438] The title compound was prepared from methyl 6-chloro-5-nitropyridinecarboxylate (A09-01) using a method similar to that described for the synthesis of A01. LCMS: MS m / z (ESI) [M+1]+=244.0.

[0439] Intermediate A10

[0440] Specification 70 / 206 pages 81 CN 121285551 A

[0441] To a solution of 5-bromo-1H-pyrazole-4-carboxynitrile (466 mg, 2.71 mmol) in dioxane (15 mL) and H2O (4 mL), A03-01 (500 mg, 1.80 mmol), XPhos Pd G3 (153 mg, 0.18 mmol), XPhos (86.0 mg, 0.18 mmol) and K3PO4 (1.15 g, 5.41 mmol) were added. The reaction was stirred at 110 °C under a N2 atmosphere for 16 hours. The reaction mixture was concentrated. The residue was ground together with EtOAc / H2O (20 ml: 10 ml) at 25 °C for 2 hours and filtered. The solid was dried under vacuum to give A10-01 (130 mg, 29.7% yield). LCMS: MS m / z (ESI) [M+H]+ = 243.1.

[0442] H2O (3 mL) and LiOH (191 mg, 4.54 mmol) were added to a solution of A10-01 (110 mg, 0.45 mmol) in THF (8 mL). The reaction was stirred at 80 °C for 12 hours. After cooling to room temperature, the reaction mixture was adjusted to pH=5 with 3 M HCl. The mixture was filtered, the solid was washed with THF (10 mL), and dried under vacuum to give A10 (100 mg, 96.5% yield). LCMS: MS m / z (ESI) [M+H]+=229.1.

[0443] Intermediate A11

[0444]

[0445] NBS (21.0 g, 118 mmol) was added to a solution of A11-01 (20 g, 118 mmol) in DMF (200 mL). The mixture was stirred at 25 °C for 3 hours. The reaction suspension was diluted with water (3 L) and extracted with EtOAc (200 mL 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 100 / 0-95 / 5) to give A11-02a (17.0 g, 58.0% yield) and A11-02b (3.0 g, 10.2% yield). A11-02a: LCMS: MS m / z (ESI) [M+H]+=248.0; H NMR (400 MHz, CDC13) δ 8.05 (d, J=7.6 Hz, 1H), 6.46 (d, J=12.0 Hz, 1H), 4.59 (brs, 2H), 3.88 (s, 3H).

[0447] A11-O2b: LCMS: MS m / z (ESI) [M+H]+=247.9; 1H NMR (400 MHz, CDCl3) δ 7.76 (t, J=8.4 Hz, 1H), 6.56 (dd, J=8.4, 1.2 Hz, 1H), 4.60 (brs, 2H), 3.91 (s, 3H).

[0448] A11 was prepared from A11-O2b using a method similar to that described for the synthesis of A07. LCMS: MS m / z (ESI) [M+1]+=260.1; 1H NMR (400 MHz, DMSO‑d 6) δ 9.82 (brs, 1H) , 9.25 (brs, 1H) , 8.70 (s, 1H) , 8.18 (d , J=8.4Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 4.48-4.37 (m, 3H).

[0449] Intermediate A12 Specification 71 / 206 pages 82 CN 121285551 A

[0450]

[0451] To a solution of A11-02a (6 g, 24.2 mmol) in dioxane (100 mL), (PinB)2 (9.2 g, 36.3 mmol), Pd(dppf)Cl2 (1.8 g, 2.42 mmol) and KOAc (5.9 g, 60.5 mmol) were added. The reaction was stirred at 100 °C under N2 atmosphere for 12 hours. The reaction mixture was concentrated under vacuum and then washed at 25 °C with EtOAc / H2O (80 ml / 20 ml) for 2 hours and filtered. The solid was dried under vacuum to give Al2-O1 (4.80 g, 67.2% yield). ¹H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J = 9.2 Hz, 1H), 6.47 (s, 2H), 6.38 (d, J = 14.4 Hz, 1H), 3.73 (s, 3H), 1.29 (s, 12H).

[0452] To a solution of 5-bromo-1-methylpyrazole-4-carboxynitrile (3.00 g, 16.1 mmol) in dioxane (100 mL) and H2O (20 mL), Al2-O1 (4.80 g, 16.1 mmol), Xphos (0.80 g, 1.61 mmol), XPhos Pd G3 (0.70 g, 0.134 mmol), and K3PO4 (8.60 g, 40.3 mmol) were added. The reaction mixture was stirred at 80 °C under a N2 atmosphere for 12 hours. The reaction mixture was concentrated under vacuum and then ground with EtOAc / H2O (60 mL / 20 mL) at 25 °C for 2 hours. The mixture was filtered, and the solid was dried under vacuum to give Al2-O2 (3.50 g, 79.1% yield). LCMS: MS m / z (ESI) [M+H]+ = 275.2; 1H NMR (400MHz, DMSO-d6) δ 8.72 (d, J=8.0 Hz, 1H), 8.27 (s, 1H), 7.56 (s, 2H), 7.28 (d, J=13.2 Hz, 1H), 4.39 (s, 3H), 3.89 (s, 3H).

[0453] Al2-O2 (3.5 g, 12.8 mmol) was reacted with THF (30 mL) and H2O (15 mL) in 15 mL of water.LiOH (5.40 g, 128 mmol) was added to a solution in mL. The reaction was stirred at 80 °C for 12 h. After cooling to room temperature, the reaction mixture was adjusted to pH=5 with 3 M HCl. The mixture was filtered, the solid was washed with THF (10 mL), and dried under vacuum to give A12 (2.7 g, 81.3% yield). LCMS: MS m / z (ESI) [M+H]+=261.0.

[0454] Intermediate A13

[0455]

[0456] The title compound was prepared from 5-bromo-1-fluoro-3-methyl-2-nitrobenzene using a method similar to that described for the synthesis of A05. LCMS: MS m / z (ESI) [M+H]+=257.3.

[0457] Intermediate A14 Specification 72 / 206 pages 83 CN 121285551 A

[0458]

[0459] A solution of A14-01 (9.5 g, 69.8 mmol) and NBS (12.42 g, 69.8 mmol) in acetonitrile (100 ml) was stirred at 65 °C under a nitrogen atmosphere for 4 hours. The reaction mixture was quenched at room temperature by adding saturated Na2S2O3 (50 mL) and NaHCO3 (50 mL). The mixture was extracted with EtOAc (100 mL x 3), the combined organic layers were washed with brine (100 mL), and dried with anhydrous Na2SO4. After filtration, the filtrate was concentrated to obtain the residue, which was eluted with PE / EtOAc (13:1) and purified by rapid silica gel chromatography to obtain A14-02 (5.46 g, 36.4% yield). LCMS: MS m / z (ESI) [M+H]+=215.0; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=6.4 Hz, 1H), 6.52 (d, J=10.4 Hz, 1H), 4.84 (brs, 2H).

[0460] 1H-pyrazole (0.76 g, 11.2 mmol) and K2CO3 (3.86 g, 27.9 mmol) were added to a solution of A14-02 (2 g, 9.30 mmol) in DMF (20 mL). The reaction was stirred at 100 °C for 16 hours. The reaction solution was diluted with H₂O (300 mL) and extracted with EtOAc (50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by rapid silica gel chromatography, eluting with PE / THF (8:1) to give A14-03 (2.02 g, 83% yield). LCMS: MS m / z(ESI) [M+H]+=263.0; 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=2.4 Hz, 1H), 7.78–7.73 (m, 2H), 7.14 (s, 1H), 6.51 (s, 1H), 4.95 (brs, 2H).

[0461] PdCl2(dppf) (562 mg, 0.768 mmol) and potassium acetate (1.51 g, 15.4 mmol) were added to a solution of Al4-O3 (2.02 g, 7.68 mmol) and (PinB)2 (2.93 g, 11.5 mmol) in 1,4-dioxane (30 mL). The reaction mixture was stirred at 100 °C for 16 hours. The mixture was filtered through a diatomaceous earth mat, the filtrate was concentrated, and the residue was eluted with PE / THF (6:1) and purified by silica gel chromatography to give compound A14-04 (1.98 g, 83% yield). LCMS: MS m / z (ESI) [M+H]+=311.1; 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=2.4 Hz, 1H), 7.99 (s, 1H), 7.76 (d, J=1.6 Hz, 1H), 6.99 (s, 1H), 6.50 (t, J=2.0 Hz, 1H), 5.45 (brs, 2H), 1.36 (s, 12H).

[0462] Pd(Ph3P)4 (0.738 g, 0.638 mmol) was added to a solution of A14-04 (1.98 g, 6.38 mmol), K2CO3 (1.765 g, 12.77 mmol), and A08-02 (6.21 g, 12.8 mmol) in 1,4-dioxane (30 mL) and water (6.00 mL). The reaction mixture was stirred at 80 °C for 12 hours. The mixture was filtered through a diatomaceous earth mat, and the filtrate was concentrated to obtain a residue. The residue was dissolved in EtOAc:H2O = 1:1 (20 mL) and stirred for 1 hour. The mixture was then filtered, and the filter cake was concentrated to obtain A14-05 (570 mg, 32.2% yield). LCMS: MS m / z (ESI) [M+H]+=278.1; 1H NMR (400 MHz, DMSO‑d 6) δ 8.45 (d, J=2.4 Hz, 1H) , 8.27 (s, 1H) , 7.87 (d, J=1.2 Hz, 1H) , 7.71 (s, 1H) , 7.23 (brs, 2H) ,6.62 (t, J=2.0 Hz, 1H), 5.37 (t, J=3.6 Hz, 2H), 5.02 (t, J=3.2 Hz, 2H). Specification 73 / 206 pages 84 CN 121285551 A

[0463] Sodium hydroxide (288 mg, 7.21 mmol) was added to a solution of A14-O5 (200 mg, 0.721 mmol) in water (3 mL). The reaction mixture was stirred in MW at 120 °C for 2.5 hours. The mixture was adjusted to pH=6 with 1M HCl. The mixture was then filtered, and the filter cake was concentrated to give A14 (110 mg, 51.5% yield). LCMS: MS m / z (ESI) [M+H]+=296.1; 1H NMR (400 MHz, DMSO‑d 6) δ 8.17 (d , J=2.4 Hz, 1H) , 8.08 (d , J= 2.4 Hz, 1H) , 7.88 (s, 1H) , 7.60 (s, 1H) , 6.92 (brs, 2H) , 6.50-6.44 (m, 1H) , 5.39 (t, J=3.2 Hz, 2H) , 5.03 (t, J=3.2 Hz, 2H).

[0464] Intermediate A15

[0465]

[0466] PinBH (6.55 ml, 45.4 mmol) was added to a solution of A15-01 (5 g, 30.3 mmol) in THF (25 ml) at 40 °C under N2 for 10 minutes, while maintaining the internal temperature below about 50 °C. The mixture was stirred at 50 °C for 1 hour and then cooled back to 25 °C. A solution of dtbbpy (812 mg, 3.03 mmol), bis(pinacol)diboron (4.61 g, 18.16 mmol), and [Ir(COD)(OMe)2] (1.00 g, 1.51 mmol) in THF (25 mL) was added to the cooled solution. The reaction was heated to 65 °C for 3 hours. The mixture was then cooled to 40 °C and quenched by adding i-PrOH (5 ml). This mixture, as a solution of A15-O2 in THF, was used directly for the next step. LCMS: MS m / z (ESI) [M+H]+=292.1.

[0467] To a solution of A15-O2 (8.00 g, 27.5 mmol) in THF (50 mL) and water (50 mL), 4-cyano-2,5-dihydrofuran-3-yl ester of 4-methylbenzenesulfonic acid, (7.00 g, 28.8 mmol) was added.1.00 g (1.37 mmol) of Pd(Xantphos)Cl2 and 17.50 g (82 mmol) of tripotassium phosphate were added. The mixture was stirred at 65 °C under N2 atmosphere for 16 h. After cooling to 25 °C, the mixture was diluted with MeCN (25 mL) and stirred for 2 h. The mixture was filtered, the solid was washed with water (20 mL) and MeCN (10 mL), and dried under vacuum to give A15-03 (1.6 g, 22.6% yield). LCMS: MS m / z (ESI) [M+H]+=258.9; 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.41 (s, 1H), 6.83 (s, 2H), 5.34 (t, J=3.2 Hz, 2H), 4.99 (t, J=3.2 Hz, 2H), 3.83 (s, 3H), 2.60 (s, 3H).

[0468] NaOH (1.6 g, 40.0 mmol) was added to a solution of Al₂O₃ (1.6 g, 6.19 mmol) in THF (8.00 mL) and water (8.00 mL). The mixture was stirred at 80 °C for 16 hours. The mixture was adjusted to pH 5 with HCl (1M). The mixture was filtered through a diatomaceous earth pad, and the residue was concentrated to give A15. LCMS: MS m / z (ESI) [M+H]+ = 245.2; 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.38 (s, 1H), 6.78 (s, 2H), 5.33 (s, 2H), 4.99 (s, 2H), 2.61 (s, 3H).

[0469] Intermediate A16

[0470]

[0471] The title compound was prepared from A16-01 using a method similar to that described for the synthesis of A15. Instructions 74 / 206 pages 85 CN 121285551 A

[0472] Intermediate A17

[0473]

[0474] NBS (23.0 mg, 129 mmol) was added to a solution of A17-01 (20.0 g, 108 mmol) in THF (200 mL). The mixture was stirred at 25 °C under N2 atmosphere for 1 hour. The mixture obtained by quenching at 25 °C by adding H2O (200 mL) was extracted with EtOAc (200 mL). The extract was obtained with 10% sodium thiosulfate solution (200 mL) and saturated sodium chloride solution (200 mL).The combined organic layers were washed sequentially with MgSO4 (mL), dried, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by rapid silica gel chromatography (0 to 5% THF / petroleum ether gradient elution @ 40 mL / min) to give A17-02 (10.0 g, 35.1% yield). LCMS: MS m / z (ESI) [M+H]+=263.9.1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 6.86 (s, 1H), 6.38 (s, 2H), 3.76 (s, 3H).

[0475] To a solution of A17-02 (10.0 g, 37.8 mmol) in dioxane (100 mL), (PinB)2 (28.8 g, 113 mmol), KOAc (11.1 g, 113 mmol) and Pd(dppf)Cl2 (401 mg, 3.78 mmol) were added. The mixture was stirred at 100 °C under a N2 atmosphere for 12 hours. The reaction mixture was quenched with H2O (100 mL) and extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Mg2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (0 to 5% EA / petroleum ether gradient elution @ 40 mL / min) to give A17-03 (8.00 g, 67.9% yield). LCMS: MS m / z (ESI) [M+H]+=312.0; 1H NMR (400 MHz, DMSO‑d6) δ 8.02 (s, 1H) , 6.74 (s, 1H) , 6.36 (s, 2H) , 3.75 (s, 3H) , 1.30 (s, 12H).

[0476] To a solution of A17-03 (6.00 g, 19.3 mmol) in dioxane (60 mL) and H2O (20 mL), A08-02 (4.68 g, 19.3 mmol), K2CO3 (7.97 g, 57.8 mmol) and Pd(PPh3)4 (2.23 g, 1.93 mmol) were added, and the mixture was stirred at 80 °C under a N2 atmosphere for 4 hours. The reaction mixture was diluted at 25 °C with EtOAc (60 mL) and H2O (60 mL), the mixture was filtered, and the filter cake was concentrated under reduced pressure to give A17-04 (4.00 g, 74.5% yield). LCMS: MS m / z (ESI) [M+H]+=279.0; 1H NMR (400 MHz, DMSO‑d6) δ 8.02 (s, 1H) , 7.60(s, 1H), 7.08 (brs, 2H), 5.35 (t, J=3.2 Hz, 2H), 5.00 (t, J=3.2 Hz, 2H), 3.86 (s, 3H).

[0477] LiOH·H2O (5.74 g, 144 mmol) was added to a solution of A17-O4 (4.00 g, 14.4 mmol) in THF (40 mL) and H2O (20 mL). The reaction was stirred at 85 °C for 4 hours. The reaction mixture was filtered to remove the black solid. The filtrate was adjusted to pH=6 with 1M HCl. The mixture was filtered, and the filter cake was concentrated under reduced pressure to obtain A17. LCMS: MS m / z (ESI) [M+H]+=265.0; 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.60 (s, 1H), 7.12 (brs, 2H), 5.36 (s, 2H), 5.01 (s, 2H).

[0478] Intermediate B01

[0479]

[0480] K2CO3 (1.86 g, 13.5 mmol) was added to a mixture of B01-01 (900 mg, 4.49 mmol) and 4-fluorobenzene-1-carboxynitrile (544 mg, 4.49 mmol) in DMSO (15 mL), and the mixture was stirred at 100 °C under N2 atmosphere for 12 hours. The reaction mixture was filtered, the filtrate was diluted with H2O (200 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel chromatography to give B01-02 (1.00 g, 73.8%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.53 (d, J=8.8 Hz, 2H), 6.62 (d, J=8.8 Hz, 2H), 3.55–3.40 (m, 2H), 3.32–3.20 (m, 2H), 2.73 (s, 3H), 2.20–2.01 (m, 2H), 1.41 (s, 9H).

[0481] 4M HCl / dioxane (4 mL) was added to a mixture of BO1-O2 (400 mg, 1.33 mmol) in DCM (4 mL), and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to give BO1 (310 mg, HCl salt). LCMS: MS m / z (ESI)[M+1]+=202.1;

[0482] Intermediate B02

[0483]

[0484] The title compound was prepared from B02-01 using a method similar to that used for the synthesis of B01. ¹H NMR (400 MHz, DMSO-d₆) δ 9.10 (br s, 2H), 7.58 (d, J=8.8 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 4.07–3.97 (m, 2H), 3.28–3.13 (m, ¹H), 2.96–2.83 (m, 2H), 2.53–2.51 (m, 3H), 2.11–2.01 (m, 2H), 1.63–1.47 (m, 2H).

[0485] Intermediate BO₃

[0486]

[0487] The title compound was prepared from BO₃-0₁ using a method similar to that described for the synthesis of BO₁. LCMS: MS m / z (ESI) [M+1]+=202.2.

[0488] Intermediate B04 Specification 76 / 206 pages 87 CN 121285551 A

[0489]

[0490] The title compound was prepared from B04-01 using a method similar to that used for the synthesis of B01. LCMS: MS m / z (ESI) [M+1]+=216.0.

[0491] Intermediate B05

[0492]

[0493] The title compound was prepared from B05-01 using a method similar to that used for the synthesis of B01. LCMS: MS m / z (ESI) [M+H]+=216.1.

[0494] Intermediate B06

[0495]

[0496] The title compound was prepared from B01-01 and 2-fluoropyridine using a method similar to that described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H]+=178.0; 1H NMR: (400 MHz, DMSO‑d 6) δ 9.74‑9.42 (m, 2H), 8.07‑7.97 (m, 2H), 7.10 (d, J=9.2 Hz, 1H), 7.00‑6.86 (m, 1H) , 4.05‑3.92 (m, 2H) , 3.90‑3.78 (m, 2H) , 3.70‑3.58 (m, 1H) , 2.60 (t, J=5.2 Hz, 3H) , 2.45‑ 2.36 (m, 2H).

[0497] Intermediates B07a and B07b, Specification 77 / 206 pages, 88 CN 121285551 A

[0498]

[0499] Bis(trimethylsilyl)aminopotassium (96.0 mL, 96.0 mmol) was added to a solution of B07-01 (10.0 g, 64.0 mmol) in THF (100 mL) at -78 °C under a N2 atmosphere. The mixture was stirred at -78 °C for 40 min, and then 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (34.3 g, 96.0 mmol) in THF (50 mL) was added. The mixture was heated to 20 °C and stirred for 16 h. The reaction mixture was quenched with saturated NH4Cl (100 mL) and then extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue (SiO2, 0 to 6% EtOAc in petroleum ether solution) was purified by column chromatography to give compound B07-02 (3.04 g, 16.5% yield). ¹H NMR: (400 MHz, CDCl3) δ 5.74–5.62 (m, 1H), 4.05–3.95 (m, 4H), 2.59–2.51 (m, 2H), 2.44–2.39 (m, 2H), 1.91 (t, J = 6.4 Hz, 2H).

[0500] TEA (6.49 mL, 46.8 mmol) and Pd(dppf)Cl2 (2.30 g, 3.12 mmol) were added to a solution of B07-02 (9.00 g, 31.2 mmol) in MeOH (90 mL). The reaction mixture was stirred at 25 °C under a CO atmosphere (50 psi) for 18 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, 0 to 2% THF in petroleum ether solution) to give compound B07-03 (3.20 g, 48.5% yield). 1H NMR: (400 MHz, CDCl3) δ 6.95–6.83 (m, 1H), 4.01 (s, 4H), 3.75 (s, 3H), 2.57–2.52 (m, 2H), 2.47–2.44 (m, 2H), 1.81 (t, J=6.4 Hz, 2H).

[0501] LiAlH4 (0.700 g, 17.7 mmol) was added to a solution of BO7-O3 (3.50 g, 17.7 mmol) in THF (50 mL) at 0 °C under a N2 atmosphere. The reaction was stirred at 0 °C for 1 h. The reaction mixture was quenched with H2O (0.7 mL) and 15% NaOH (0.7 mL) was added.The sample was dried with Mg2SO4, filtered, and concentrated under reduced pressure to give crude product B07-04 (2.90 g, 96.5%). 1H NMR: (400 MHz, chloroform-d) δ=5.65-5.57 (m, 1H), 4.04 (s, 2H), 3.99 (s, 4H), 2.34-2.23 (m, 4H), 1.80 (t, J=6.5 Hz, 2H).

[0502] To a solution of B07-04 (1.50 g, 8.81 mmol) in THF (30 mL), 2-bromophenol (1.80 g, 10.6 mmol) and PPh3 (3.50 g, 13.2 mmol) were added, followed by the slow addition of DIAD (2.70 g, 13.2 mmol) at 0 °C under a N2 atmosphere. The mixture was stirred at 25 °C for 16 hours. The residue was quenched with H2O (50 mL) and extracted with EtOAc (50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, 0, about 10% petroleum ether solution of EtOAc) to give compound B07-05 (1.80 g, 62.8% yield). LCMS: MS m / z (ESI) [M+H]+=324.8; 1H NMR: (400 MHz, CDCl3) δ 7.55 (dd, J=7.6, 1.6 Hz, 1H), 7.32–7.25 (m, 1H), 6.91 (dd, J=8.4, 1.2 Hz, 1H), 6.85 (td, J=7.6, 1.2 Hz, 1H), 5.87–5.75 (m, 1H), 4.50 (s, 2H), 4.02 (s, 4H), 2.46–2.31 (m, 4H) (See specification page 78 / 206, CN 121285551 A) , 1.86 (t, J=6.4 Hz, 2H).

[0503] Hydrogenated tri-n-butyltin (1.72 g, 5.91 mmol) and AIBN (100 mg, 0.492 mmol) were added to a solution of B07-05 (1.60 g, 4.92 mmol) in toluene (20 mL), and the reaction was stirred at 100 °C for 1 hour. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL). The combined organic layers were washed with brine (30 mL).The residue was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, 0, approximately 40% EtOAc in petroleum ether solution) to give compound B07-06 (900 mg, 74.3% yield). 1H NMR: (400 MHz, CDCl3) δ 7.20 (dd, J=7.6, 1.2 Hz, 1H), 7.16 (td, J=7.6, 1.2 Hz, 1H), 6.90 (td, J=7.6, 0.8 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 4.41 (s, 2H), 4.01 (s, 4H), 2.09-1.98 (m, 2H), 1.91-1.81 (m, 4H), 1.74-1.65 (m, 2H).

[0504] AcOH (8 mL, 139 mmol) was added to a solution of B07-06 (800 mg, 3.25 mmol) in H2O (10 mL). The reaction was stirred at 60 °C for 5 hours. The reaction mixture was concentrated, the residue was diluted with an aqueous solution of NaHCO3 (20 mL), and extracted with EtOAc (10 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude product B07-07 (600 mg, 91.3% yield). LCMS: MS m / z (ESI) [M+H]+=203.0.

[0505] Methylamine hydrochloride (451 mg, 6.67 mmol) was added to a solution of B07-07 (270 mg, 1.34 mmol) in MeOH (5 mL) at 25 °C for 1 hour, followed by the addition of sodium cyanoboride (168 mg, 2.67 mmol). The reaction was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, 0-10% MeOH in DCM solution) to give a mixture of compounds B07a and B07b for the next step. LCMS: MS m / z (ESI) [M+H]+=217.9.

[0506] Intermediates B08a and B08b

[0507]

[0508] n-BuLI (2.5 M, in hexane, 9.41 mL, 23.5 mmol) was slowly added to a solution of B08-01 (2 g, 10.7 mmol) in THF (20 mL) at -78 °C. The mixture was stirred at -78 °C for 30 minutes, and then slowly added to a solution of B08-01 (2 g, 10.7 mmol) in THF (5 mL) at -78 °C.1,4-dioxanespiro[4.5]dec-8-one (1.70 g, 10.7 mmol) was extracted with ethyl acetate (40 mL), and the reaction mixture was then heated to 0 °C. The reaction was stirred at 0 °C for 2 h. The reaction was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (40 mL), and the combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (0 to 18% THF / petroleum ether gradient elution @ 40 mL / min) to give B08-02 (1.82 g, 64.4% yield). LCMS: MS m / z (ESI) [M+Na]+=287.2; 1H NMR (400 MHz, CD3OD) δ 7.48–7.41 (m, 2H), 7.26–7.19 (m, 2H), 4.92 (s, 2H), 3.97 (s, 4H), 2.23–2.06 (m, 4H), 1.98–1.91 (m, 2H), 1.70–1.60 (m, 2H).

[0509] Compound B08-02 (1.82 g, 6.89 mmol) was dissolved in TFA (23 mL), and the reaction was stirred overnight at 30 °C. The reaction was cooled to -20 °C, and THF (4.6 mL) was added. The pH was adjusted to approximately 11 by carefully adding NaOH (25 wt%, aqueous solution). H₂O (4.6 mL) was added to induce precipitation. The solution was filtered and thoroughly washed with H₂O. The resulting solid was concentrated under reduced pressure. The crude product was purified by rapid silica gel chromatography (0 to 2% THF / petroleum ether gradient elution @ 25 mL / min) to give B08-03 (0.91 g, 65.3% yield). ¹H NMR (400 MHz, CD₃OD) δ 7.35–7.18 (m, 4H), 5.15 A (s, 2H), 2.97–2.82 (m, 2H), 2.39–2.17 (m, 4H), 2.14–2.05 (m, 2H).

[0510] To a solution of B08-03 (280 mg, 1.38 mmol) in MeOH (6 mL), a 30 wt% methylamine / MeOH solution (6 mL, 6.92 mmol) was added. The reaction mixture was stirred for 1 hour, and then NaBH3CN (174 mg, 2.77 mmol) was added. The resulting mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. [The remaining text appears to be incomplete and requires further context.]The residue was purified by rapid silica gel chromatography (0 to 4% MeOH / DCM gradient elution @ 25 mL / min) to give a mixture of B08a and B08b for the next step. LCMS: MS m / z (ESI) [M+H]+=218.0;

[0511] Intermediate B09

[0512]

[0513] Potassium allyl trifluoroborate (9.00 g, 60.5 mmol) and TsOH (1.00 g, 6.05 mmol) were added to a solution of B09-01 (4.00 g, 30.3 mmol) in toluene (50 mL). The reaction was stirred at 40 °C for 16 h. The reaction solution was diluted with H2O (40 mL) and extracted with DCM (40 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give B09-02 (5.20 g, 98.7% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.35–7.17 (m, 4H), 6.08–5.96 (m, 1H), 5.31–5.19 (m, 2H), 3.13 (d, J=16.4 Hz, 2H), 2.99 (d, J=16.4 Hz, 2H), 2.56 (d, J=7.2 Hz, 2H), 2.42 (s, 1H).

[0514] Br2 (2.80 g, 17.2 mmol) was added dropwise to a solution of B09-02 (3.00 g, 17.2 mmol) in DCM (20 mL) at -30 °C for 20 minutes. The reaction was stirred at 0 °C for 20 minutes. The reaction solution was quenched with NaHSO3 (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give B09-03 (5.30 g, 92.1% yield).

[0515] K2CO3 (4.10 g, 29.9 mmol) was added to a solution of B09-03 (5.00 g, 15.0 mmol) in MeOH (30 mL). The reaction was stirred at 25 °C for 4 hours. The reaction mixture was filtered and concentrated under vacuum to give B09-04 (3.1 g, 81.8% yield). ¹H NMR (400 MHz, CD3OD) δ 7.22–7.07 (m, 4H), 4.68–4.59 (m, 1H), 4.24 (dd, J=10.4, 5.2 Hz, 1H), 4.02 (dd, J=10.4, 4.0 Hz, 1H), 3.26 (dd, J= 43.6, 16.0 Hz,2H), 3.07 (dd, J=28.4, 16.0 Hz, 2H), 2.73 (dd, J=14.4, 7.2 Hz, 1H), 2.47 (dd, J=14.4, 4.0 Hz, 1H).

[0516] MeNH2 / THF (10 mL, 59.3 mmol) was added to a solution of B09-04 (1.50 g, 5.93 mmol) in EtOH (5 mL). The reaction was stirred at 65 °C for 12 hours. The reaction mixture was concentrated under vacuum and purified by silica gel chromatography (SiO2, DCM / MeOH=100 / 0-20 / 1) to give B09 (410 mg, 34.0% yield). 1H NMR (400MHz, CDCl3‑d) δ 7 .24‑7 .08 (m , 4H) , 4.03 (dd , J=9.2, 6.4 Hz, 1H) , 3.70 (dd , J=9.2, 4.8 Hz, 1H) , 3.49‑3.39 (m, 1H) , 3.23 (d, J=16.4 Hz, 1H), 3.14 (d, J=15.6 Hz, 1H), 3.11 (d, J=16.4 Hz, 1H), 2.96 (d, J=16.0 Hz, 1H), 2.44 (s, 3H), 2.32 (dd, J= Instructions 80 / 206 Page 91 CN 121285551 A 7.5, 12.8, 7.6 Hz, 1H), 1.87 (dd, J=12.8, 5.2 Hz, 1H).

[0517] Intermediate B10

[0518]

[0519] The title compound was prepared from B10-01 using a method similar to that used in the synthesis of B09. LCMS: MS m / z (ESI) [M+H]+=156.1;

[0520] Intermediate B11

[0521]

[0522] The title compound was prepared from 4,4-difluorocyclohexane-1-one (B11-01) using a method similar to that used in the synthesis of B09. 1H NMR: (400MHz, DMSO-d6) δ 4.00–3.76 (m, 3H), 2.53 (s, 3H), 2.25–2.16 (m, 1H), 2.09–1.66 (m, 8H), 1.60–1.48 (m, 1H).

[0523] Intermediate B12

[0524]

[0525] BO1-01 (200 mg, 0.999 mmol) was reacted with dioxane (4Bromobenzene (0.13 mL, 1.199 mmol), BINAP (124 mg, 0.200 mmol), Pd2(dba)3 (91.5 mg, 0.100 mmol), and Cs2CO3 (651 mg, 2.00 mmol) were added to a solution containing bromobenzene (0.13 mL, 1.199 mmol), BINAP (124 mg, 0.200 mmol), Pd2(dba)3 (91.5 mg, 0.100 mmol), and Cs2CO3 (651 mg, 2.00 mmol). After degassing and purging with N2 three times, the reaction was stirred at 100 °C for 12 hours. The crude product (SiO2, petroleum ether / EtOAc = 100 / 0-10 / 1) was purified by column chromatography to give compound B12-01 (193 mg, 0.698 mmol, 69.9%). LCMS: MS m / z (ESI) [M+H]+=277.4.

[0526] The compound of B12-01 (193 mg, 0.698 mmol) was dissolved in 4 M HCl / 1,4-dioxane (4.00 mL, 129 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum to give the desired product B12 (140 mg, 0.658 mmol, 94.25% yield, HCl salt). LCMS: MS m / z (ESI) [M+H]+=177.0; 1H NMR: (400 MHz, CDCl3) δ 10.32 (brs, 1H), 10.12 (brs, 1H), 7.72 (d, J=7.6 Hz, 2H), 7.54–7.42 (m, 2H), 7.41–7.35 (m, 1H), 4.47–4.28 (m, 2H), 4.26–4.17 (m, 1H), 4.16–4.06 (m, 1H), 3.92–3.80 (m, 1H), 2.98–2.84 (m, 1H), 2.78 (s, 3H), 2.73–2.59 (m, 1H).

[0527] Intermediate B13

[0528]

[0529] Cs2CO3 (1.46 g, 4.49 mmol) and RuPhos Pd G3 (125 mg, 0.15 mmol) were added to a solution of B01-01 (300 mg, 1.50 mmol) and 3-bromopyridine (355 mg, 2.25 mmol) in THF (6 mL). The resulting mixture was stirred at 80 °C under N2 atmosphere for 12 hours. The reaction mixture was diluted with H2O (50 mL), extracted with EtOAc (90 mL), the organic layer was dried with MgSO4, filtered, and concentrated. The residue (SiO2,DCM / THF=100 / 0-2 / 1), yielding compound B13-01 (400 mg, 1.44 mmol, 96.3%). LCMS: MS m / z (ESI) [M+H]+= 278.1; 1H NMR (400MHz, DMSO‑d6) δ 7.96 (d , J=2.8 Hz, 1H) , 7.87 (d , J=4.0 Hz, 1H) , 7.16 (dd , J=8.4 , 4.4 Hz, 1H), 6.93 (dd, J=8.4, 1.6 Hz, 1H), 4.90-4.65 (m, 1H), 3.50-3.37 (m, 2H), 3.28-3.16 (m, 2H), 2.74 (s, 3H), 2.21-1 .99 (m , 2H) , 1.42 (s, 9H).

[0530] A solution of B13-01 (250 mg, 0.90 mmol) in 4 M HCl / dioxane (7 mL) was stirred at 30 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give compound B13 (160 mg, crude). LCMS: MS m / z (ESI) [M+H]+=178.1.

[0531] Intermediate B14

[0532]

[0533] The title compound was prepared from (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (B14-01) and 3-iodo-1-methyl-1H-pyrazole using a method similar to that described for the synthesis of B13. LCMS: MS m / z (ESI) [M+H]+=179.1.

[0534] Intermediate B15

[0535]

[0536] The title compound was prepared from (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (B15-01) and 3-iodo-1-methyl-1H-pyrazole using a method similar to that described for the synthesis of B13. LCMS: MS m / z (ESI) [M+H]+=179.1. Specification 82 / 206 pages 93 CN 121285551 A

[0537] Intermediate B16

[0538]

[0539] The title compound was prepared from tert-butyl 2,5-diazabicyclo[2.2.1]octane-2-carboxylate (B16-01) and 3-iodo-1-methyl-1H-pyrazole using a method similar to that used in the synthesis of B13.

[0540] Intermediate B17

[0541]

[0542] The title compound was prepared from 3-iodo-1-methyl-1H-pyrazole using a method similar to that used in the synthesis of B13.

[0543] Intermediate B18

[0544]

[0545] To a solution of B01-01 (500 mg, 2.50 mmol) in i-PrOH (9 mL), 5-iodo-1-methylpyrazole (623 mg, 3.00 mmol), ethylene glycol (884 mg, 2.50 mmol), K3PO4 (2.12 g, 9.98 mmol) and CuI (95.1 mg, 0.499 mmol) were added. The mixture was stirred at 100 °C under a N2 atmosphere for 16 hours. After cooling to room temperature, the mixture was diluted with water (15 mL) and EtOAc (15 mL). The aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product (SiO2, 0-3% tetrahydrofuran in petroleum ether solution) was purified by column chromatography to give compound B18-01 (450 mg, 64.3% yield). LCMS: MS m / z (ESI) [M+H]+=281.3.

[0546] HCl / dioxane (4 M, 2 mL, 8.00 mmol) was added to a solution of B18-01 (450 mg, 1.61 mmol) in dioxane (1 mL). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated to give compound B18 (260 mg, 90% yield).

[0547] Intermediate B19 Specification 83 / 206 pages 94 CN 121285551 A

[0548]

[0549] To a solution of B01-01 (616 mg, 3.08 mmol) in THF (25 mL), 2-bromo-1-methylimidazole (450 mg, 2.80 mmol), BrettPhosPdG3 (253 mg, 0.280 mmol), Brettphos (150 mg, 0.280 mmol) and t-BuONa (806 mg, 8.39 mmol) were added. The mixture was stirred at 50 °C under N2 protection for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by rapid silica gel chromatography (0 to 40% THF / petroleum ether gradient elution @ 100 mL / min) to give B19-01 (350 mg, 87.5% yield). LCMS: MS m / z (ESI) [M+H]+=280.9.

[0550] A solution of B19-01 (400 mg, 1.427 mmol) in 4 M HCl / dioxane (5 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give B19 (281 mg, 1.427 mmol)mg, crude). LCMS: MS m / z (ESI) [M+H]+= 181.2.

[0551] Intermediate B20

[0552]

[0553] The title compound was prepared from 1-fluoro-4-(trifluoromethyl)benzene using a method similar to that used in the synthesis for BO1. LCMS: MS m / z (ESI) [M+H]+= 245.4;

[0554] Intermediate B21

[0555]

[0556] The title compound was prepared from 2,4-difluorobenzyl nitrile using a method similar to that used in the synthesis for BO1. LCMS: MS m / z (ESI) [M+H]+=219.9; 1H NMR: (400 MHz, DMSO‑d 6) δ 9.26 (brs, 2H) , 7 .68‑7 .55 (m , 1H) , 6.60 (dd , J=13.2, 2.0 Hz, 1H) , 6.50 (dd , J=8.8, 2.0 Hz, 1H) , 3.95‑3.80 (m, 1H) , 3.70‑3.61 (m, 1H) , 3.59‑3.49 (m, 2H) , 3.43‑3.37 (m, 1H) , 2.60 (s, 3H) , 2.41‑2.30 (m, 1H), 2.29–2.19 (m, 1H).

[0557] Intermediate B22 Specification 84 / 206 pages 95 CN 121285551 A

[0558]

[0559] The title compound was prepared from 4-fluoro-2-methylbenzyl nitrile using a method similar to that described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H]+=216.0; 1H NMR: (400 MHz, DMSO‑d 6) δ 9.43 (brs, 2H) , 7.49 (d, J=8.8 Hz, 1H) , 6.55 (d, J=2.0 Hz, 1H) , 6.48 (dd, , 2.38 (s, 3H) , 2.36–2.29 (m, 1H), 2.29–2.18 (m, 1H).

[0560] Intermediate B23

[0561]

[0562] The title compound was prepared from 4-chloropyridine hydrochloride using a method similar to that described for the synthesis of B01.LCMS: MS m / z (ESI) [M+H]+=178.0;

[0563] Intermediate B24

[0564]

[0565] The title compound was prepared from 1-fluoro-4-(methylsulfonyl)benzene using a method similar to that used in the synthesis for BO1. LCMS: MS m / z (ESI) [M+H]+=255.0;

[0566] Intermediate B25

[0567] Specification 85 / 206 pages 96 CN 121285551 A

[0568] The title compound was prepared from 1-(cyclopropylsulfonyl)-4-fluorobenzene using a method similar to that used in the synthesis for BO1. LCMS: MS m / z (ESI) [M+H]+=281.1;

[0569] Intermediate B26

[0570]

[0571] The title compound was prepared from 2,4-difluoro-1-(methanesulfonyl)benzene using a method similar to that described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H]+=272 .9; 1H NMR (400 MHz, DMSO‑d 6) δ 9 .31 (brs, 2H) , 7.58 (t, J=8.4 Hz, 1H) , 6.58 (dd, J=14.4, 2.0 Hz, 1H) , 6.52 (dd, J =8.8, 2.0 Hz, 1H) , 3.95‑3.84 (m, 1H) , 3.70‑3.62 (m, 1H) , 3.56 (s, 3H) , 3.55‑ 3.48 (m, 1H) , 3.43‑3.34 (m, 2H) , 3.17 (s, 3H) , 2.42–2.31 (m, 1H), 2.30–2.18 (m, 1H).

[0572] Intermediate B27

[0573]

[0574] The title compound was prepared from 4-bromo-2-methyl-1-(methanesulfonyl)benzene using a method similar to that used in the synthesis of B13. LCMS: MS m / z (ESI) [M+1]+=268.9.

[0575] Intermediate B28

[0576]

[0577] The title compound was prepared from 1,2-difluoro-4-(methanesulfonyl)benzene using a method similar to that used in the synthesis of B01. LCMS: MS m / z (ESI) [M+H]+=272.9;

[0578] Intermediate B29 Specification 86 / 206 pages 97 CN 121285551 A

[0579]

[0580] The title compound was prepared from 1-(cyclobutylsulfonyl)-4-fluorobenzene using a method similar to that described for the synthesis of B01. LCMS:MS m / z (ESI) [M+H]+=295.3;

[0581] Intermediate B30

[0582]

[0583] To a solution of B30-01 (709 mg, 3.53 mmol) in isopropanol (5 mL), (1S,2S)-2-aminocyclohexyl-1-ol (31.3 mg, 0.272 mmol), NaHMDS (5.16 mL, 5.16 mmol) and NiI2 (0.01 mL, 0.272 mmol) were added, degassed with N2 for 5 minutes, and then 3-iodooxetane (500 mg, 2.72 mmol) was added. The mixture was then heated at 80 °C under microwave radiation for 30 minutes. After cooling to room temperature, the mixture was quenched with saturated NH4Cl solution (5 ml) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (5 ml), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product (SiO2, tetrahydrofuran / petroleum ether = 0 / 100–1 / 99) was purified by column chromatography to give compound B30-02 (550 mg, 76.0% yield). 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 5.09 (dd, J=8.4, 6.0 Hz, 2H), 4.73 (t, J=6.4 Hz, 2H), 4.24‑4.14 (m, 1H).

[0584] To a solution of B30-02 (388 mg, 1.82 mmol) in dioxane (3.5 mL), add BO1-01 (350 mg, 1.75 mmol), BINAP (218 mg, 0.349 mmol), Cs2CO3 (1.71 g, 5.24 mmol), and Pd2(dba)3 (160 mg, 0.175 mmol). Stir the mixture at 120 °C under a N2 atmosphere for 2 hours. After cooling to room temperature, dilute the mixture with water (2 mL) and EtOAc (2 mL). Extract the aqueous layer with EtOAc (10 mL x 3). Wash the combined organic layers with brine (5 mL), dry with anhydrous Na2SO4, filter, and concentrate. The crude product (SiO2, petroleum ether / tetrahydrofuran = 100 / 0-10 / 1) was purified by column chromatography to give compound B30-03 (369 mg, 63.5% yield). LCMS: MS m / z (ESI) [M+H]+ = 333.2.

[0585] To B30-03 (100 mg, 0.301TFA (0.5 mL, 6.58 mmol) was added to a solution in DCM (1 mL). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated to give B30. LCMS: MS m / z (ESI) [M+H]+ = 232.8.

[0586] Intermediate B31 Specification 87 / 206 pages 98 CN 121285551 A

[0587]

[0588] The title compound was prepared from 1-bromo-4-cyclopropylbenzene using a method similar to that described for the synthesis of B12. LCMS: MS m / z (ESI) [M+H]+=440.9; 1H NMR (400 MHz, CD3OD) δ 8.22 (s, 1H) , 7.82 (s, 1H) , 7.56 (d , J=8.0 Hz, 1H) , 7.49 (d , J=8.4 Hz, 1H) , 6.92 (d , J=8.4 Hz, 2H) , 6.55 (d , J=8.4 Hz, 2H) , 4.75‑4.50 (m, 1H) , 3.65‑3.38 (m, 3H) , 3.23‑3.10 (m , 1H) , 3.08 (s , 3H) , 3.05 (s , 3H), 2.39–2.24 (m, 2H), 1.85–1.72 (m, 1H), 0.89–0.77 (m, 2H), 0.58–0.45 (m, 2H).

[0589] Intermediate B32

[0590]

[0591] The title compound was prepared from 4-bromo-2-methylpyridine using a method similar to that used in the synthesis of B13. LCMS: MS m / z (ESI) [M+H]+=192.3.

[0592] Intermediate B33

[0593]

[0594] The title compound was prepared from 3-bromo-5-methylpyridine using a method similar to that used in the synthesis of B13.

[0595] Intermediate B34

[0596]

[0597] To a solution of B01-01 (500 mg, 2.496 mmol) in CH3CN (14 mL), 4-chloro-1,2-diazine hydrochloride (377 mg, 2.50 mmol) and DIPEA (2.07 mL, 12.5 mmol) were added. The mixture was stirred at 80 °C for 18 hours. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (column, 50 to 80% ethyl acetate / petroleum ether gradient elution @ [Note: The last part of the text appears to be a reference to a product label and is not translated.]The reaction mixture was stirred at 100 mL / min to give B34-01 (620 mg, 89.2% yield). LCMS: MS m / z (ESI) [M+H]+=279.2.

[0598] A solution of B34-01 (500 mg, 1.796 mmol) in 4 M HCl / dioxane (5 mL) was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give compound B34. LCMS: MS m / z (ESI) [M+H]+=179.2.

[0599] Intermediate B35

[0600]

[0601] 3,6-dichloro-1,2-diazine (372 mg, 2.50 mmol) and DIPEA (1.65 mL, 9.99 mmol) were added to a solution of B01-01 (500 mg, 2.50 mmol) in CH3CN (5 mL), and the mixture was stirred at 90 °C for 16 hours. The reaction was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluting with 30 to 50% THF / petroleum ether) to give B35-01 (780 mg, 99.9% yield). LCMS: MS m / z (ESI) [M+H]+=313.1.

[0602] Pd / C (10%, 40.0 mg) was added to a solution of B35-01 (400 mg, 1.28 mmol) in methanol (10 mL) under N2 atmosphere. The suspension was degassed and purged three times with H2. The mixture was stirred at 20 °C for 16 hours under H2 (15 Psi). The reaction was filtered and concentrated under reduced pressure to give B35-02 (350 mg, crude). LCMS: MS m / z (ESI) [M+H]+= 279.2.

[0603] A solution of B35-02 (300 mg, 1.078 mmol) in 4 M HCl / dioxane (4 mL) was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give B35 (230 mg, crude). LCMS: MS m / z (ESI) [M+H]+= 179.1.

[0604] Intermediate B36

[0605]

[0606] The title compound was prepared from 2-chloropyrimidine using a method similar to that described for the synthesis of B34. LCMS: MS m / z (ESI) [M+H]+= 179.2.

[0607] Intermediate B37

[0608]

[0609] 4-fluorobenzene-1-carboxynitrile (149 mg, 1.23 mmol) and K2CO3 (512 mg, 3.70 mmol) were added to a solution of B37-01 (252 mg, 1.23 mmol) in DMSO (5 mL). The mixture was then heated in 100 mL of water.Stir at ℃ for 16 hours. Dilute the reaction solution with 50 mL of H2O (page 89 / 206 of the instruction manual, CN 121285551 A) and extract with ethyl acetate (50 mL). Wash the combined organic layers with brine (20 mL), dry with anhydrous Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by rapid silica gel chromatography (0 to 25% THF / petroleum ether gradient elution @ 100 mL / min) to give B37-02 (140 mg, 37.1%). LCMS: MS m / z (ESI) [M+H]+=306.2.

[0610] NaH (23.0 mg, 0.575 mmol, 60% purity) was added to a solution of B37-02 (117 mg, 0.383 mmol) in THF (3 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and CH3I (0.07 mL, 1.15 mmol) was added. The mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched by adding H2O (40 mL) and extracted with ethyl acetate (60 mL). The combined organic layers were washed with brine (20 mL), dried with Na2SO4, filtered, and concentrated under reduced pressure to give compound B37-03 (102 mg, 83.4% yield). LCMS: MS m / z (ESI) [M+H]+=320.2.

[0611] A solution of B37-03 (70.0 mg, 0.219 mmol) in HCl / dioxane (4 mol / L, 4 mL) was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give B37 (52.0 mg, crude). LCMS: MS m / z (ESI) [M+H]+=220.1

[0612] Intermediate B38

[0613]

[0614] The title compound was prepared from ((3S,4R)-4-fluoropyrrolidine-3-yl)carbamate using a method similar to that described for the synthesis of B37.

[0615] Intermediate B39

[0616]

[0617] To a solution of B39-01 (3.9 g, 20.9 mmol) in DMSO (10 mL), 4-bromopyridine (2.41 mL, 25.1 mmol), BINAP (2.6 g, 4.19 mmol), Pd2(dba)3 (1.9 g, 2.09 mmol) and Cs2CO3 (13.6 g, 41.9 mmol) were added. The resulting mixture was stirred at 100 °C under a N2 atmosphere for 12 hours. After cooling to room temperature, the reaction mixture was diluted with H2O (60 mL) and EtOAc (60 mL) was added.3) Extraction: The organic layer was dried with Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 0-10 / 1) to obtain B39-02 (4.85 g, 88.0% yield). LCMS: MS m / z (ESI) [M+1]+=263.9; 1H NMR (400 MHz, DMSO‑d 6) δ 8.07 (d, J=6.0 Hz, 2H) , 7.23 (d, J=6.4 Hz, 1H) , 6.42 (d, J=6.4 Hz, 2H) , 4.19‑4.07 (m, 1H) , 3.54‑ 3.45 (m, 1H) , 3.38‑3.34 (m, 1H) , 3.29‑3.20 (m, 1H) , 3.07 (dd, J=10.4, 4.8 Hz, 1H) , 2.23‑2.03 (m, 1H) , 1.95-1.80 (m, 1H), 1.39 (s, 9H).

[0618] NaH (98.7 mg, 2.47 mmol) was added to a solution of B39-02 (500 mg, 1.90 mmol) in DMF (8 mL), and the mixture was stirred at 20 °C for 10 minutes, and then iodoethane (0.18 mL, 2.28 mmol) was added. The resulting mixture was stirred at 20 °C for 12 hours. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (90 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, DCM / MeOH=100 / 0-10 / 1) to give B39-03 (260 mg, 47.0% yield). LCMS: MS m / z (ESI) [M+1]+=291.9; 1H NMR (400 MHz, DMSO‑d 6) δ 8.09 (d , J=6.0 Hz, 2H) , 6.47 (br d , J=6.0 Hz, 2H) , 4.74‑4.37 (m, 1H) , 3.46‑3.42 (m, 2H) , 3.30‑3.20 (m, 1H) , 3.19‑3.11 (m, 3H) , 2.18‑2.07 (m, 2H) , 1.41 (s, 9H) , 1.06 (t, J=7.2 Hz, 3H).

[0619] Compound B39-03 (260 mg, 0.892 mg)The 1,000 mmol) was dissolved in HCl / dioxane (4.00 mol / L, 8.00 mL), and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and dried under vacuum to give B39 (161 mg, crude). LCMS: MS m / z (ESI) [M+H]+=192.3.

[0620] Intermediate B40

[0621]

[0622] The title compound was prepared from 1-iodo-3-(trifluoromethyl)benzene using a method similar to that described for the synthesis of B13.

[0623] Intermediate B41

[0624]

[0625] To a solution of B41-01 (1.00 g, 4.80 mmol) in dioxane (8 mL) and water (2 mL), 1,4-dibromobenzene (1.25 g, 5.29 mmol), K2CO3 (2.00 g, 14.4 mmol) and Pd(PPh3)4 (0.550 g, 0.480 mmol) were added. The mixture was stirred at 80 °C under a N2 atmosphere for 3 hours. After cooling to room temperature, the mixture was diluted with water (5 mL) and EtOAc (5 mL). The aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product (SiO2, ethyl acetate / petroleum ether = 0 / 100-36 / 64) was purified by column chromatography to give B41-02 (1.0 g, 87.8% yield). LCMS: MS m / z (ESI) [M+H]+ = 237.0.

[0626] To a solution of B41-02 (500 mg, 2.11 mmol) in THF (10 mL), BO1-01 (465 mg, 2.32 mmol), t-BuONa (608 mg, 6.33 mmol) and RuPhos Pd G3 (177 mg, 0.211 mmol) were added. The mixture was stirred at 80 °C under N2 atmosphere for 16 hours. After cooling to room temperature, the reaction mixture was diluted with H2O (2 mL), extracted with EtOAc (20 mL), the organic layer was dried with Na2SO4, filtered, and concentrated. The residue (SiO2, DCM / MeOH = 100 / 0-95 / 5) was purified by column chromatography to obtain B41-03 (45 mg, 6.0% yield). LCMS: MS m / z (ESI) [M+H]+ = 357.2. Specification 91 / 206 pages 102 CN 121285551 A

[0627] HCl / dioxane (4 M, 0.5 mL) was added to a solution of B41-03 (45 mg, 0.126 mmol) in dioxane (1 mL).2.00 mmol). The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated to give B41 (35 mg, 94.7% yield).

[0628] Intermediate B42

[0629]

[0630] The title compound was prepared from 3-bromo-2-methylbenzyl nitrile using a method similar to that described for the synthesis of B12. LCMS: MS m / z (ESI) [M+H]+=216.1.

[0631] Intermediate B43

[0632]

[0633] A solution of NBS (7.50 g, 42.3 mmol) in dioxane (50 mL) was slowly added to a solution of B43-01 (5.00 g, 42.3 mmol) in dioxane (50 mL) at room temperature for 30 minutes. The mixture was stirred at room temperature for another 30 minutes. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (eluting with 0 to 22% ethyl acetate / petroleum ether) to give B43-02 (2.54 g, 30.5% yield). LCMS: MS m / z (ESI) [M+Na]+ = 196.7; 1H NMR (400 MHz, DMSO-d6) δ 7.23 (dd, J=8.4, 7.6 Hz, 1H), 7.08–7.04 (m, 1H), 7.04–7.01 (m, 1H), 5.87 (s, 2H).

[0634] K3PO4 (12.9 g, 60.9 mmol) and cataCXium A Pd G3 (73.9 mg, 0.101 mmol) were added to a mixture of B43-02 (4.00 g, 20.3 mmol), cyclopropylborondiol (3.50 g, 40.6 mmol), toluene (40 mL), and H2O (20 mL). The mixture was then stirred at 90 °C under a N2 atmosphere for 16 hours. The reaction mixture was extracted with EtOAc (20 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (eluting with 0 to 10% EA / petroleum ether) to give B43-03 (3.12 g, 97.1%). LCMS: MS m / z (ESI) [M+H]+=158.8; 1H NMR (400 MHz, CDCl3) δ Specification 92 / 206 pages 103 CN 121285551 A 7.13-7.06 (m, 1H), 7.01 (d, J=6.8 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 4.23 (brs,2H), 1.81–1.66 (m, 1H), 1.21–1.08 (m, 2H), 0.85–0.74 (m, 2H).

[0635] A mixture of B43-O3 (3.12 g, 19.7 mmol) in 2M H2SO4 (48 mL) was heated to dissolve the solid, and then cooled in an ice bath. A solution of sodium nitrite (1.40 g, 20.7 mmol) in H2O (10 mL) was slowly added to the compound, and the mixture was stirred in an ice bath for 30 minutes. Then, a solution of NaI (3.50 g, 23.7 mmol) in H2O (10 mL) was slowly added at 0 °C for 30 minutes, and the mixture was stirred at 20 °C for 30 minutes. The reaction mixture was diluted with H2O (60 mL) and extracted with EtOAc (60 mL 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by rapid silica gel chromatography (eluting with 0 to 2% EA / petroleum ether) to give B43-04 (3.00 g, 56.5%). ¹H NMR (400 MHz, CDCl₃) δ 8.07 (dd, J=8.0, 1.2 Hz, 1H), 7.62 (dd, J=7.6, 1.2 Hz, 1H), 7.01 (dd, J=8.0, 7.6 Hz, 1H), 2.01–1.89 (m, 1H), 1.37–1.26 (m, 2H), 0.94–0.84 (m, 2H).

[0636] Pd2(dba)3 (0.300 g, 0.372 mmol), BINAP (0.500 g, 0.743 mmol), and Cs2CO3 (3.60 g, 11.2 mmol) were added to a solution of B43-04 (1.00 g, 3.72 mmol) and B01-01 (0.700 g, 3.72 mmol) in dioxane (5 mL). The mixture was stirred at 120 °C under a N2 atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by rapid silica gel chromatography (eluting with 0 to 10% EA / petroleum ether) to give B43-05 (1.2 g, 92.3% yield). LCMS: MS m / z (ESI) [M+H]+=342.2.

[0637] Compound B43-05 (1.20 g, 3.51 mmol) was dissolved in HCl / dioxane (4 M, 12 mL), and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give B43 (1.00 g, 3.51 mmol).g, crude product). LCMS: MS m / z (ESI) [M+H]+=242.2.

[0638] Intermediate B44

[0639]

[0640] Potassium allyl trifluoroborate (17.8 g, 121 mmol) and 4-methylbenzenesulfonic acid (2.10 g, 12.1 mmol) were added to a solution of B44-01 (7.90 g, 60.3 mmol) in toluene (100 mL), and the reaction was stirred at 20 °C for 16 hours. The reaction solution was diluted with H2O (100 mL) and extracted with ethyl acetate (100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give crude product B44-02 (7.50 g, 71.9% yield). ¹H NMR (400MHz, CDCl₃) δ 7.63 (d, J=7.2 Hz, 2H), 7.47 (d, J=7.6 Hz, 2H), 5.86–5.68 (m, 1H), 5.24–5.11 (m, 2H), 4.86–4.77 (m, 1H), 2.60–2.38 (m, 2H), 2.23 (brs, 1H).

[0641] Potassium osmium (VI) dihydrate (0.60 g, 1.73 mmol) and NMO (2.20 g, 19.1 mmol) were added to a solution of B44-02 (3.00 g, 17.3 mmol) in acetone (15 mL) and water (4.5 mL). The mixture was stirred at 20 °C for 16 hours. The mixture was quenched with a saturated aqueous solution of Na2S2O3 (50 mL) and extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluting with 40 to 50% THF / petroleum ether) to give B44-03 (0.90 g, 26.9% yield). ¹H NMR (400MHz, DMSO-d₆) δ 7.85–7.74 (m, 2H), 7.60–7.42 (m, 2H), 5.50–5.35 (m, 1H), 4.90–4.74 (m, 1H), 4.67–4.43 (m, 2H), 3.34–3.17 (m, 3H), 1.76–1.56 (m, 2H).

[0642] 4-methylbenzenesulfonyl chloride (977 mg, 5.12 mmol) was added to a solution of B44-O3 (900 mg, 4.66 mmol) in DCM (54 mL).mmol), TEA (0.71 mL, 5.12 mmol) and di-n-butyltin oxide (116 mg, 0.466 mmol). The mixture was stirred at 45 °C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluting with 30 to 40% THF / petroleum ether) to give B44-04 (850 mg, 96.4% yield).

[0643] TEA (2.20 mL, 15.9 mmol) and methanesulfonic anhydride (1.47 g, 8.457 mmol) were added to a solution of B44-04 (1.00 g, 5.285 mmol) in DCM (10 mL). The mixture was stirred at 20 °C for 2 hours. The mixture was quenched with H2O (10 mL) and extracted with DCM (10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give B44-05 (1.00 g, 70.8% yield).

[0644] The mixture of B44-05 (1.00 g, 3.741 mmol) was dissolved in methylamine / ethanol solution (10.55 g, 30% purity), and the mixture was stirred at 60 °C for 16 hours. The resulting mixture was concentrated. The residue was purified by rapid silica gel chromatography (eluting with 10 to 30% methanol / DCM @ 40 mL / min), followed by preparative HPLC (alkaline conditions, column: C18-1 150 30 mm 5 μm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 14%-54%, 9 min) to give B44 (56.0 mg, 7.4% yield). LCMS: MS m / z (ESI) [M+H]+=203.1.

[0645] Intermediate B45

[0646]

[0647] NaBH4 (1.00 g, 26.4 mmol) was slowly added to a solution of B45-01 (2.00 mg, 8.80 mmol) in MeOH (40 mL) at 25 °C under N2 atmosphere. The reaction was stirred at 25 °C for 2 hours. The reaction mixture was quenched with H2O (40 mL) and concentrated under reduced pressure to remove MeOH. The resulting solution was extracted with EtOAc (30 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give B45-02 (2.00 mg, 99.1% yield). LCMS: MS m / z (ESI) [M+H-t-Bu]+= Specification 94 / 206 pages 105 CN 121285551 A 174.0; 1H NMR (400MHz, DMSO-d 6) δ 4.90 (d , J=3.2 Hz,1H), 4.33–4.25 (m, 1H), 3.97–3.82 (m, 3H), 3.82–3.72 (m, 2H), 3.60 (dd, J=9.2, 1.6 Hz, 1H), 2.13–2.02 (m, 2H), 1.37 (s, 9H).

[0648] A solution of B45-02 (2.00 g, 8.72 mmol) in 5% TFA / HFIP (2 mL) was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give crude product B45-03 (2.10 g, crude product).

[0649] Iodobenzene (2.37 g, 11.6 mmol), CuI (295 mg, 1.55 mmol), L-proline (356 mg, 3.10 mmol), and Cs2CO3 (6.30 g, 19.4 mmol) were added to a solution of B45-03 (1.00 g, 7.74 mmol) in DMSO (30 mL). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by rapid silica gel chromatography (20 g silica gel column, elution of 0 to 68% ethyl acetate / petroleum ether gradient @ 30 mL / min) to give B45-04 (400 mg, 25.2% yield). LCMS: MS m / z (ESI) [M+H]+=206.2; 1H NMR (400MHz, DMSO‑d 6) δ 7.21‑7.02 (m, 2H), 6.68 (t, J=7.2 Hz, 1H), 6.43 (d, J=7.6, 2H), 4.96 (d , J=2.8 Hz, 1H) , 4.34 (brs, 1H) , 3.97‑3.86 (m, 2H) , 3.83 (dd , J=9.2, 4.4 Hz, 1H) , 3.77 (d, J=8.0 Hz, 1H) , 3.71 (d, J=8.0 Hz, 1H) , 3.65 (dd, J=9.2, 2.0 Hz, 1H), 2.17 (d, J=3.6 Hz, 2H).

[0650] TEA (0.47 mL, 3.41 mmol) was added to a solution of B45-04 (350 mg, 1.70 mmol) in DCM (7 mL), followed by the addition of mesylate anhydride (475 mg, 2.73 mmol) to DCM (3 mL).The resulting mixture was stirred at 0 °C for 1 hour. The reaction mixture was diluted with H2O (10 mL), concentrated under reduced pressure to remove DCM, and extracted with EtOAc (8 mL 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give crude product B45-05 (460 mg, 95.2% yield). LCMS: MS m / z (ESI) [M+H]+=284.3; 1H NMR (400MHz, CDCl3) δ 7.29‑ 7.17 (m, 2H) , 6.82 (t, J=7.6 Hz, 1H) , 6.54 (d , J=8.0 Hz, 2H) , 5.41‑5.32 (m, 1H) , 4.22‑4.17 (m, 1H) , 4.16‑4.12 (m, 1H) , 4.09‑4.04 (m, 1H) , 4.04‑3.98 (m, 2H) , 3.96 (d, J=8.0 Hz, 1H) , 3.10 (s, 3H) , 2.76 (d, J = 14.4 Hz, 1H), 2.46 (dd, J = 14.4, 5.6 Hz, 1H).

[0651] CH3NH2 (30%, in EtOH) (549 mg, 17.6 mmol) was added to a solution of B45-05 (500 mg, 1.76 mmol) in EtOH (9 mL). The reaction was stirred at 60 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (silica gel rapid column, 0 to 6% MeOH (NH3) / DCM gradient elution @ 30 mL / min) to give B45 (300 mg, 77.9% yield). LCMS: MS m / z (ESI) [M+H]+=219.3; 1H NMR (400MHz, CDCl3) δ 7.25‑7.18 (m, 2H) , 6.77 (t, J=7.2 Hz, 1H) , 6.48 (d , J= 7.6 Hz, 2H) , 4.10‑3.95 (m, 4H), 3.94-3.83 (m, 2H), 3.64-3.53 (m, 1H), 2.56 (s, 3H), 2.55-2.47 (m, 1H), 2.42-2.31 (m, 1H).

[0652] Intermediate B46

[0653] Specification 95 / 206 pages 106 CN 121285551 A

[0654] To B46-01 (3.004-fluorobenzyl-1-carboxynitrile (5.90 g, 48.5 mmol) and potassium carbonate (11.7 g, 85.0 mmol) were added to a mixture in DMSO (60 mL). The resulting mixture was stirred at 100 °C for 2.5 h. After cooling to room temperature, the reaction mixture was diluted with H2O (100 mL), extracted with EtOAc (100 mL), the organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 100 / 0-4 / 1) to give B46-02 (985 mg, 21.6% yield). LCMS: MS m / z (ESI) [M+H]+=188.8; 1H NMR (400 MHz, DMSO‑d 6) δ 7.52 (d, J=8.8 Hz, 2H) , 6.58 (d, J=8.8 Hz, 2H) , 5.03 (d, J=3.6 Hz, 1H) , 4.47‑4.37 (m, 1H) , 3.48‑3.35 (m, 3H) , 3.14 (d, J=10.8 Hz, 1H) , 2.11‑1.98 (m, 1H) , 1.96‑1.84 (m, 1H).

[0655] TEA (1.15 mL, 8.29 mmol) and methanesulfonic anhydride (1.16 g, 6.63 mmol) were added to a solution of B46-02 (780 mg, 4.15 mmol) in DCM (20 mL). The resulting mixture was stirred at 0 °C under a N2 atmosphere for 1 hour. The reaction mixture was filtered and dried under vacuum to give B46-03 (1.00 g, 90.6% yield). LCMS: MS m / z (ESI) [M+H]+=266.9.

[0656] Cyclopropylamine (800 mg, 14.0 mmol) and K2CO3 (545 g, 3.94 mmol) were added to a solution of B46-03 (350 mg, 0.413 mmol) in THF (7 mL). The reaction mixture was stirred at 80 °C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with 50 mL of H₂O, extracted with 50 mL of EtOAc, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (SiO₂, PE / EA = 100 / 0–10 / 1) to give B46 (96 mg, 32.1% yield). LCMS: MS m / z (ESI) [M+H]⁺ = 227.9; 1H NMR (400 MHz, DMSO–d₆) δ 7.51 (d, J = 8.8).Hz, 2H) , 6.56 (d , J=8.8 Hz, 2H) , 3.51‑3.41 (m , 2H) , 3.41‑3.35 (m , 1H) , 3.31‑3.23 (m, 1H) , 3.15‑3.05 (m, 1H) , 2.49‑2.36 (m, 1H) , 2.17‑2.03 (m, 2H) , 1.95‑1.82 (m, 1H) , 0.46‑0.34 (m, 2H) , 0.28‑0.13 (m, 2H).

[0657] Intermediate B47

[0658]

[0659] 4-fluorobenzene-1-carboxynitrile (2.2 g, 18.3 mmol) and potassium carbonate (4.40 g, 31.9 mmol) were added to a solution of B39-01 (1.7 g, 9.13 mmol) in DMSO (35 mL). The reaction mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with H2O (40 mL), extracted with EtOAc (50 mL 3), the organic layer was dried with Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (eluting with 27 to 35% PE / EA @ 80 mL / min) to give B47-01 (1.91 g, 72.9% yield). LCMS: MS m / z (ESI) [M+H]+=287.9; 1H NMR (400 MHz, DMSO‑d 6) δ 7 .51 (d , J=8.8 Hz , 2H) , 7 .24 (d , J=6 .4 Hz , 2H) , 6 .58 (d , J=8.8 Hz , 2H) , 4.20‑4.09 (m, 1H) , 3.56‑3.47 (m, 1H) , 3.46‑3.38 (m, 1H) , 3.34‑3.24 (m, 1H) , 2.21‑2.09 (m, 1H) , 1.95‑1.84 (m, 1H) , 1.39 (s, 9H).

[0660] NaH (90.5 mg, 2.26 mmol) was slowly added to a solution of B47-01 (500 mg, 1.74 mmol) in DMF (10 mL) at 0 °C. The mixture was stirred at 0 °C for 10 minutes, and then (bromomethyl)cyclopropane (0.33 mL, 3.48 mmol) was added. The resulting mixture was stirred at room temperature under a N2 atmosphere for 12 hours. The reaction mixture was quenched with H2O (100 mL). (Instructions for use 96 / 206 pages, 107 CN 121285551 A) with EtOAc (100 mL)3) Extraction, drying the organic layer with Na2SO4, filtration, and concentration. Purification of the residue by column chromatography (SiO2, PE / EA=5 / 1) yielded B47-02 (415 mg, 69.9% yield). LCMS: MS m / z (ESI) [M+H]+= 341.9.

[0661] The compound B47-02 (415 mg, 1.22 mmol) was dissolved in HCl / dioxane (4 mol / L, 8 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give B47 (285 mg, crude product). LCMS: MS m / z (ESI) [M+1]+=241.9.

[0662] Intermediate B48

[0663]

[0664] 4-iodobenzene-1-carboxynitrile (157 mg, 0.684 mmol), Cs2CO3 (669 mg, 2.05 mmol) and RuPhos Pd G3 (55.2 mg, 0.066 mmol) were added to a solution of B48-01 (152 mg, 0.684 mmol) in THF (20 mL). The mixture was stirred at 80 °C under N2 atmosphere for 16 hours. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (20 to 40% THF / petroleum ether gradient elution @ 100 mL / min) to give B48-02 (201 mg, 90.8% yield). LCMS: MS m / z (ESI) [M-t-Bu+H]+=268.1.

[0665] NaH (37.1 mg, 0.928 mmol) was added to a solution of B48-02 (200 mg, 0.619 mmol) in THF (4 mL) at 0 °C, and the mixture was stirred at 0 °C for 30 min. CH3I (0.12 mL, 1.86 mmol) was added, and the mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with H2O (20 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give B48-03 (200 mg, 95.8% yield). LCMS: MS m / z (ESI) [M-t-Bu+H]+=282.1.

[0666] A solution of B48-03 (200 mg, 0.593 mmol) in HCl / dioxane (4 M, 8 mL) was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give B48 (150 mg, crude). LCMS: MS m / z (ESI) [M+H]+= 238.2.

[0667] Intermediate B49

[0668]

[0669] CuI (46.0 mg, 0.241 mmol), K3PO4 (1.03 g, 4.83 mmol), and N1,N1,N2,N2-tetramethylethyl-1,2-diamine (21.3 mg, 0.241 mmol) were added to a solution of B49-01 (580 mg, 2.90 mmol) and 4-iodobenzyl-1-carboxynitrile (553 mg, 2.41 mmol) in dioxane (6 mL). The mixture was stirred at 100 °C under a N2 atmosphere for 18 hours. The mixture was diluted with water (25 mL) and extracted with EtOAc (25 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product (petroleum ether / instructions 97 / 206 page 108 CN 121285551 A EtOAc= 10 / 1-3 / 1) was purified by silica gel column chromatography to give B49-02 (720 mg, 99.0% yield). LCMS: MS m / z (ESI) [M+H]+= 302.1; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J=8.8 Hz, 2H), 7.66 (d, J=7.2 Hz, 2H), 4.85 (brs, 1H), 4.51‑4.36 (m, 1H) , 4.21‑4.15 (m, 1H) , 3.77 (dd , J=10.0, 3.2 Hz, 1H) , 3.02 (dd , J=17 .6, 8.0 Hz, 1H) , 2.55 (dd , J=17 .6, 4.8 Hz, 1H), 1.46 (s, 9H).

[0670] NaH (51.8 mg, 1.29 mmol) was added dropwise to a solution of B49-02 (300 mg, 0.996 mmol) in DMF (3 mL) at 0 °C. The mixture was stirred at 0 °C for 10 min, and then CH3I (184 mg, 1.29 mmol) was added. The mixture was stirred at 25 °C for 12 h. The mixture was quenched with NH4Cl (20 mL) and then extracted with EtOAc (20 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 10 / 1-3 / 1) to give B49-03 (230 mg, 73.2% yield). LCMS: MS m / z (ESI)[M+H]+=316.1.

[0671] A solution of B49-03 (230 mg, 0.729 mmol) in 4M HCl / dioxane (4 mL) was stirred at 25 °C for 18 hours. The solution was concentrated to give B49 (120 mg, 76.4% yield). LCMS: MS m / z (ESI) [M+H]+= 216.1.

[0672] Intermediate B50

[0673]

[0674] The title compound was prepared from 4-fluoro-3-methylbenzylnitrile using a method similar to that described for the synthesis of B01. 1H NMR (400 MHz, DMSO‑d 6) δ 9.10 (br s, 2H) , 7.58 (d, J=8.8 Hz, 2H) , 7.05 (d , J=8.8 Hz, 2H) , 4.07‑3.97 (m, 2H) , 3.28‑3.13 (m, 1H) , 2.96‑2.83 (m, 2H) , 2.53‑ 2.51 (m, 3H) , 2.11‑2.01 (m, 2H) , 1.63‑1.47 (m, 2H).

[0675] Intermediate B51

[0676]

[0677] 3-bromo-4-fluorobenzene-1-carboxynitrile (749 mg, 3.74 mmol) and K2CO3 (1.04 g, 7.49 mmol) were added to a solution of B01-01 (500 mg, 2.50 mmol) in DMF (10 mL). The mixture was stirred at 100 °C for 2.5 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL 3). The organic phase was separated, washed with brine (10 mL 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (0 to 7% EA / petroleum ether gradient elution @ 25 mL / min) to give B51-01 (1.00 g, 98.0% yield). LCMS: MS m / z (ESI) [M-t-Bu+H]+=324.2. Specification 98 / 206 pages 109 CN 121285551 A

[0678] H2O (3 mL), K3PO4 (168 mg, 0.789 mmol), and cataCXium A Pd G3 (19.2 mg, 26.0 µmol) were added to a solution of B51-01 (100 mg, 0.263 mmol), cyclopropylborondiol (45.2 mg, 0.526 mmol), and toluene (6 mL). The mixture was heated at 90 °C.The mixture was stirred at ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (0 to 6% EtOAc / petroleum ether gradient elution @ 18 mL / min) to give B51-02 (90 mg, 90.2% yield). LCMS: MS m / z (ESI) [M+H]+=342.2

[0679] The compound B51-02 (90.0 mg, 0.264 mmol) was dissolved in HCl / dioxane (4 M, 5 mL), and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give crude product B51 (80 mg, 98.4% yield). LCMS: MS m / z (ESI) [M+H]+=242.2.

[0680] Intermediate B52

[0681]

[0682] The title compound was prepared from 3,4-difluorobenzyl nitrile using a method similar to that used in the synthesis of B01. LCMS: MS m / z (ESI) [M+1]+=219.9;

[0683] Intermediate B53

[0684]

[0685] The title compound was prepared from iodobenzene using a method similar to that used in the synthesis of B12. LCMS: MS m / z (ESI) [M+H]+=176.9.

[0686] Intermediate B54

[0687]

[0688] Pd(dppf)Cl2 (115 mg, 0.158 mmol), Cs2CO3 (1.03 g, 3.16 mmol), and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborhexacyclopentane (398 mg, 2.37 mmol) were added to a solution of B51-01 (600 mg, 1.58 mmol) in H2O (2 mL) and dioxane (10 mL). The reaction was stirred at 100 °C under a N2 atmosphere for 12 hours. After cooling to room temperature, the reaction mixture was diluted with H2O (20 mL), extracted with EtOAc (20 mL 3), the organic layer was dried with anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 8 / 1, page 99 / 206, CN 121285551 A) to give B54-01 (258 mg, 47.9% yield). LCMS: MS m / z (ESI) [M+H]+=341.9.

[0689] 10% Pd / C (5 mg, 0.0470 mmol) was added to the solution of B54-01 (50 mg, 0.146 mmol) in EtOAc (1 mL). The reaction was carried out at room temperature under an H2 atmosphere (15Stir for 12 hours (psi). Filter the mixture through a diatomaceous earth pad and concentrate the filtrate to give B54-02 (35.0 mg, 69.6% yield). LCMS: MS m / z (ESI) [M+H]+=344.0; 1H NMR (400 MHz, DMSO‑d 6) δ 7.61 (d , J=1.6 Hz, 1H) , 7.48 (dd , J=8.4, 1.6 Hz, 1H) , 6.99 (d , J=8.4 Hz, 2H), 4.75‑4.60 (m, 1H), 3.33‑3.20 (m, 4H), 3.02‑2.91 (m, 1H), 2.79 (s, 3H), 2.17‑2.05 (m, 2H), 1.41 (s, 9H), 1 .15 (d , J=5.6

[0690] A solution of B54-02 (35.0 mg, 0.102 mmol) dissolved in HCl / dioxane (4 M, 2 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give B54 (23 mg, 92.7% yield). LCMS: MS m / z (ESI) [M+H]+=243.9.

[0691] Intermediate B55

[0692]

[0693] Pd(PPh3)2Cl2 (81.8 mg, 0.105 mmol) and CuI (20.0 mg, 0.105 mmol), ethynyl[tris(prop-2-yl)]silane (192 mg, 1.052 mmol) were added to a solution of B51-01 (400 mg, 1.05 mmol) in TEA (10 mL), and the mixture was stirred at 80 °C under N2 protection for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (elution gradient of 20 to 40% THF / petroleum ether @ 50 mL / min) to give B55-01 (400 mg, 78.9% yield). LCMS: MS m / z (ESI) [M+H]+=482.3;

[0694] A mixture of B55-01 (370 mg, 0.768 mmol) in HCl / dioxane (4 M, 10 mL) was stirred at 20 °C for 1 hour. The reaction was concentrated under reduced pressure to give B55 (320 mg, 99.7% yield). LCMS: MS m / z (ESI) [M+H]+=382.3.

[0695] Intermediate B56

[0696]

[0697] 4-fluoro-3-formylbenzyl nitrile (500 mg, 3.35 mmol) was stirred in DMSO (10 mL) for 1 hour.B01-01 (672 mg, 3.35 mmol) and K2CO3 (1.39 g, 10.1 mmol) were added to a solution in mL. The mixture was stirred at 100 °C for 16 hours. The reaction solution was diluted with H2O (50 mL), extracted with ethyl acetate (100 mL), and the combined organic layers were washed with brine (50 mL). The mixture was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (40 to 50% THF / petroleum ether gradient elution @ 100 mL / min) to give B56-01 (1.06 g, 96.0% yield). Instructions for Use 100 / 206 pages 111 CN 121285551 A LCMS: MS m / z (ESI) [M+H]+ =330.2.

[0698] DAST (2.45 mg, 15.2 mmol) was slowly added to a solution of B56-01 (500 mg, 1.52 mmol) in DCM (10 mL), and the resulting mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched by adding H2O (10 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (30% THF / petroleum ether gradient elution @ 100 mL / min) to give B56-02 (521 mg, 97.6% yield). LCMS: MS m / z (ESI) [M+H]+ = 352.2.

[0699] A mixture of B56-02 (750 mg, 2.13 mmol) in HCl / dioxane (4 M, 18 mL) was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give B56 (500 mg, 81.4% yield). LCMS: MS m / z (ESI) [M+H]+ = 252.1.

[0700] Intermediate B57

[0701]

[0702] NaH (159 mg, 3.98 mmol) was slowly added to a solution of B49-02 (200 mg, 0.664 mmol) in DMF (4 mL) at 0 °C. The mixture was stirred at 0 °C for 30 minutes, and then MeI (565 mg, 3.98 mmol) was added. The mixture was stirred at 25 °C for 12 hours. The mixture was quenched with NH4Cl (10 mL) and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = ...100 / 0-1 / 1), yielding B57-01 (200 mg, 87.7% yield). LCMS: MS m / z (ESI) [M+1]+=344.2; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=8.8 Hz, 2H), 7.69 (d, J=8.8 Hz, 2H), 4.91-4.38 (m, 1H), 4.29-4.08 (m, 1H), 3.82-3.61 (m, 1H), 2.86-2.52 (m, 3H), 1.48 (s, 9H), 1.31 (s, 3H), 1.18 (s, 3H).

[0703] A solution of B57-01 (200 mg, 0.634 mmol) in HCl / dioxane (3 mL) was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure to give B57 (92.0 mg, 64.9%). LCMS: MS m / z (ESI) [M+H]+=244.1.

[0704] Intermediate B58

[0705] Specification 101 / 206 pages 112 CN 121285551 A

[0706] At 0 °C, TEA (0.29 mL, 2.08 mmol) was added to a solution of B58-01 (210 mg, 1.04 mmol) in DCM (4 mL), followed by benzyl chloroformate (0.19 mL, 1.35 mmol). The reaction solution was heated to 25 °C and stirred for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the residue. The residue was purified by rapid silica gel chromatography (12 g silica gel column, elution gradient from 0 to 37% THF / petroleum ether @ 30 mL / min) to give B58-02 (340 mg, 97.4% yield). LCMS: MS m / z (ESI) [M+H‑Boc]+=237.1; 1H NMR (400MHz, CDCl3) δ 7.44‑7.28 (m, 5H) , 5.19‑5.07 (m, 2H) , 5.07‑4.96 (m, 1H) , 4.39‑4.27 (m, 1H) , 4.25‑4.09 (m, 1H) , 3.92‑3.78 (m, 1H) , 3.66‑3.48 (m, 2H) , 3.31‑3.11 (m, 1H) , 1.46 (s, 9H).

[0707] B58-02 (310 mg, 0.922 mmol) and CH3I (392 mg, 2.76 mmol) were added to DMF (6NaH (147 mg, 3.69 mmol) was added to the solution in mL. The reaction solution was stirred at 25 °C for 16 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution (20 mL) and extracted with EtOAc (15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by rapid silica gel chromatography (12 g silica gel column, 0 to 20% THF / petroleum ether gradient elution @ 30 mL / min) to give B58-03 (260 mg, 77.4% yield). LCMS: MS m / z (ESI) [M‑Boc+H]+=265.3; 1H NMR (400MHz, CDCl3) δ 7.42‑7.29 (m, 5H) , 5.23‑5.08 (m, 2H) , 4.78‑4.39 (m, 1H) , 4.03‑3.87 (m, 1H) , 3.72‑3.54 (m, 3H) , 3.53‑3.47 (m, 1H) , 3.34 (s, 3H) , 2.91 (s, 3H) , 1.48 (s, 9H).

[0708] Pd / C (336 mg, 0.316 mmol) was added to a solution of B58-03 (230 mg, 0.631 mmol) in MeOH (5 mL). The suspension was stirred at 25 °C for 16 hours under H2 (50 psi). The reaction mixture was concentrated under reduced pressure to give B58-04 (140 mg, 96.3% yield). 1H NMR (400MHz, CDCl3) δ 4.84-4.34 (m, 1H), 4.00-3.76 (m, 1H), 3.35-3.28 (m, 3H), 3.13-3.02 (m, 2H), 2.97-2.93 (m, 1H), 2.93-2.84 (m, 3H), 2.79-2.54 (m, 1H), 1.48 (s, 9H).

[0709] Under a N2 atmosphere, 4-iodobenzene-1-carboxynitrile (143 mg, 0.625 mmol), Cs2CO3 (509 mg, 1.56 mmol), and RuPhos Pd G3 (7.30 mg, 9.00 µmol) were added to a solution of B58-04 (120 mg, 0.521 mmol) in THF (2.5 mL). The reaction was stirred at 80 °C under a N2 atmosphere for 16 hours. The reaction solution was diluted with H2O (10 mL) and EtOAc (8 mL) was added.3) Extraction. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by rapid silica gel chromatography (4 g silica gel column, 0 to 12% ethyl acetate / petroleum ether gradient elution @ 18 mL / min) to give B58-05 (140 mg, 81.1% yield). LCMS: MS m / z (ESI) [M+H]+=331.9; 1H NMR (400MHz, CDCl3) δ 7.51 (d, J=8.8 Hz, 2H), 6.54 (d, J=8.8 Hz, 2H), 5.00‑4.57 (m, 1H), 4.19‑4.05 (m , 1H) , 3.63‑3.50 (m , 3H) , 3.45‑3.38 (m , 1H) , 3.41 (s , 3H) , 2.95 (s, 3H) , 1.52 (s, 9H).

[0710] The compound of B58-05 (120 mg, 0.362 mmol) was dissolved in HCl / dioxane (4 M, 1.2 mL). The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give B58 (110 mg, crude). LCMS: MS m / z (ESI) [M+H]+ = 231.9.

[0711] Intermediate B59

[0712] Specification 102 / 206 pages 113 CN 121285551 A

[0713] 4-iodobenzene-1-carboxynitrile (231 mg, 1.01 mmol), Cs2CO3 (821 mg, 2.521 mmol) and RuPhos Pd G3 (12.4 mg, 15.0 µmol) were added to a solution of B59-01 (170 mg, 0.840 mmol) in THF (4 mL). The mixture was stirred at 80 °C under N2 atmosphere for 16 hours. The reaction mixture was filtered, concentrated under reduced pressure, and the residue was obtained. The residue was purified by rapid silica gel chromatography (0 to 45% THF / petroleum ether gradient elution @ 100 mL / min) to give B59-02 (90.0 mg, 35.3% yield). LCMS: MS m / z (ESI) [M+H]+=304.4.

[0714] NaH (26.4 mg, 0.659 mmol) and CH3I (93.5 mg, 0.659 mmol) were added to a solution of B59-02 (40.0 mg, 0.132 mmol) in DMF (1 mL). The reaction solution was stirred at 25 °C for 16 hours. The resulting mixture was poured into ice water (10Extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated NaCl aqueous solution (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give B59-03 (40.0 mg, crude). LCMS: MS m / z (ESI) [M+H]+=332.2.

[0715] A solution of B59-03 (40.0 mg, 0.121 mmol) in HCl / dioxane (4 M, 2 mL) was stirred at 20 °C for 1 hour. The reaction was concentrated under reduced pressure to give B59 (32.0 mg, crude). LCMS: MS m / z (ESI) [M+H]+=232.2.

[0716] Intermediate B60

[0717]

[0718] A solution of B47-01 (3.00 g, 10.4 mmol) in HCl / dioxane (4 M, 30 mL) was stirred at 20 °C for 1 h. The reaction was filtered, and the filter cake was dried under high vacuum to give B60-01 (1.4 g, 60.0% yield).

[0719] TEA (0.37 mL, 2.68 mmol), oxadiazon-3-carbaldehyde (100 mg, 1.16 mmol) and sodium cyanoboride (168 mg, 2.68 mmol) were added to a solution of B60-01 (200 mg, 0.894 mmol) in methanol (4 mL), and the mixture was stirred at 20 °C for 16 h. The reaction was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (20 to 40% THF / petroleum ether gradient elution @ 50 mL / min) to give B60 (159 mg, 69.1% yield). LCMS: MS m / z (ESI) [M+H]+=258.2.

[0720] Intermediate B61

[0721]

[0722] 3-(bromomethyl)-1,1-difluorocyclobutane (496 mg, 2.68 mmol), potassium iodide (371 mg, 2.24 mmol), and DIPEA (1.85 mL, 11.2 mmol) were added to a solution of B60-01 (500 mg, 2.24 mmol) in DMF (6 mL). The mixture was stirred at 85°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by rapid silica gel chromatography (elution gradient of 0 to 40% ethyl acetate / petroleum ether @ 100 mL / min) to give B61 (600 mg, 92.2% yield). LCMS: MS m / z (ESI) [M+H]+=292.2.

[0723] Intermediate B62

[0724]

[0725] The title compound was prepared from 4-(bromomethyl)tetrahydro-2H-pyran using a method similar to that used in the synthesis of B61. LCMS: MS m / z (ESI) [M+H]+=286.1.

[0726] Intermediate B63

[0727]

[0728] The title compound was prepared from 4,4-difluorocyclohexane-1-carboxaldehyde using a method similar to that used in the synthesis of B60. LCMS: MS m / z (ESI) [M+H]+=320.1; 1H NMR (400MHz, DMSO‑d 6) δ 7.51 (d, J=8.8 Hz, 2H) , 6.58 (d , J=8.8 Hz, 2H) , 3.51‑3.42 (m, 1H) , 3.42‑3.20 (m, 3H) , 3.11‑ 3.00 (m, 1H) , 2.49‑2.39 (m, 2H) , 2.15‑1.90 (m, 4H) , 1.88‑1.66 (m, 4H) , 1.57‑ 1.40 (m, 1H) , 1.22‑1.07 (m, 2H).

[0729] Intermediate B64 Specification 104 / 206 pages 115 CN 121285551 A

[0730]

[0731] The title compound was prepared from 3,3-difluorocyclobut-1-amine using a method similar to that used in the synthesis of B46. LCMS: MS m / z (ESI) [M+H]+=277.9.

[0732] Intermediate B65

[0733] ​​

[0734] The title compound was prepared from tetrahydro-2H-pyran-4-amine using a method similar to that used in the synthesis of B46. LCMS: MS m / z (ESI) [M+H]+=272.1.

[0735] Intermediate B66

[0736]

[0737] The title compound was prepared from 4,4-difluorocyclohexane-1-one using a method similar to that used in the synthesis of B60. LCMS: MS m / z (ESI) [M+H]+=306.1.

[0738] Intermediate B67 Specification 105 / 206 pages 116 CN 121285551 A

[0739]

[0740] The title compound was prepared from bicyclo[1.1.1]pentane-1-amine hydrochloride using a method similar to that used in the synthesis of B46. LCMS: MS m / z (ESI) [M+H]+=254.1.

[0741] Intermediate B68

[0742]

[0743] The title compound was prepared from (iodomethyl)cyclohexane using a method similar to that used in the synthesis of B61. LCMS: MS m / z(ESI) [M+H]+=284.2.

[0744] Intermediate B69

[0745]

[0746] LiAlH4 (3.43 mL, 8.56 mmol) was slowly added to a solution of B69-01 (800 mg, 7.14 mmol) in THF (16 mL) at 0 °C under a N2 atmosphere. The reaction mixture was stirred at 0 °C for 1 hour. The combined mixture was slowly quenched at 0 °C with water (0.33 mL), 15% NaOH (0.99 mL), and water (0.33 mL). The mixture was dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure to give B69-02 (6.52 mmol, 91.4% yield). ¹H NMR (400 MHz, CDCl₃) δ 3.54 (s, 2H), 2.55 (s, 1H), 1.75 (s, 6H).

[0747] TEA (3.62 mL, 26.1 mmol) and methanesulfonic anhydride (3.63 g, 20.9 mmol) were slowly added to a solution of B69-02 (640 mg, 6.52 mmol) in DCM (10 mL) at 0 °C. The reaction was stirred at 0 °C for 1 hour. The reaction mixture was then quenched with H₂O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, concentrated, and the residue was purified by column chromatography (SiO₂, petroleum ether / THF=100 / 0- [Instructions 106 / 206, page 117, CN 121285551 A 11 / 1]) to give B69-03 (888 mg, 77.2% yield). ¹H NMR (400 MHz, CDCl₃) δ 4.14 (s, 2H), 3.01 (s, 3H), 2.57 (s, 1H), 1.84 (s, 6H).

[0748] B69 was prepared from B69-O3 using a method similar to that used for the synthesis of B47. ¹H NMR (400 MHz, DMSO-d₆) δ 9.52–9.06 (m, 2H), 7.58 (d, J=8.8 Hz, 2H), 6.65 (d, J=8.8 Hz, 2H), 3.98–3.86 (m, 1H), 3.72–3.49 (m, 4H), 3.07 (t, J=5.6 Hz, 2H), 2.51 (s, 1H), 2.42–2.27 (m, 2H), 1.86 (s, 6H).

[0749] Intermediate B70

[0750]

[0751] NaH (0.800 g, 20.9 mmol) was slowly added to a solution of B47-01 (1.00 g, 3.48 mmol) in DMF (10.0 mL) at 0 °C under a N2 atmosphere. After stirring the reaction for 15 minutes, 2,2-dimethylethylene oxide (2.50 g, 34.8 mmol) was slowly added at 0 °C. The reaction was then warmed to room temperature and stirred for 12 hours. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 2 / 1) to give B70-01 (300 mg, 30.2% yield). LCMS: MS m / z (ESI) [M+H]+=285.9.

[0752] 4M NaOH (1.31 mL, 5.26 mmol) was added to a solution of B70-01 (300 mg, 1.05 mmol) in EtOH (2.0 mL), and the reaction was stirred at 65 °C for 12 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF=2 / 1) to give B70 (70.0 mg, 25.7% yield). LCMS: MS m / z (ESI) [M+H]+=259.9.

[0753] Intermediate B71

[0754]

[0755] TEA (5.89 mL, 42.5 mmol) and pyridine sulfur trioxide (4.23 g, 26.6 mmol) were added to a solution of B46-02 (1.00 g, 5.31 mmol) in DMSO (10 mL). The mixture was stirred at 20 °C for 16 hours. The reaction mixture was quenched by adding H2O (50 mL). Then it was extracted with EtOAc (50 mL 3). The combined organic layers were washed with brine (30 mL) and dried with Na2SO4. The reaction mixture was concentrated under reduced pressure to give the residue. The residual compound was purified by rapid silica gel chromatography (0 to 40% ethyl acetate / petroleum ether gradient elution @ 100 mL / min) to give B71-01 (300 mg, 30.3% yield). LCMS: MS m / z (ESI) [M+H]+=187.1.

[0756] To B71-01 (240 mg,(Aminocyclopropyl)methanol hydrochloride (239 mg, 1.93 mmol), TEA (0.27 mL, 1.93 mmol), and NaBH3CN (243 mg, 3.87 mmol) were added to a solution of 1.29 mmol in MeOH (5 mL). The mixture was stirred at 20 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (elution gradient of 0 to 30% ethyl acetate / petroleum ether @ 100 mL / min) to give B71 (300 mg, 90.5% yield). LCMS: MS m / z (ESI) [M-56+H]+=258.2.

[0757] Intermediate B72

[0758]

[0759] The title compound was prepared from 3,4-difluorobenzyl nitrile and 2,2-difluoroethyl trifluoromethanesulfonate using a method similar to that used in the synthesis of B47. LCMS: MS m / z (ESI) [M+1]+=270.0.

[0760] Intermediate B73

[0761]

[0762] The title compound was prepared from 1-fluoro-2-iodobenzene using a method similar to that used in the synthesis of B13. LCMS: MS m / z (ESI) [M+H]+=195.2.

[0763] Intermediate B74

[0764]

[0765] The title compound was prepared from 2-bromo-1,3-difluorobenzene using a method similar to that used in the synthesis of B19. LCMS: MS m / z (ESI) [M+H]+=213.4.

[0766] Intermediate B75 Specification 108 / 206 pages 119 CN 121285551 A

[0767]

[0768] The title compound was prepared from (bromomethyl)cyclopropane using a method similar to that described for the synthesis of B47. LCMS: MS m / z (ESI) [M+H]+=260.3.

[0769] Intermediate B76

[0770]

[0771] LiAlH4 (2.5 mol / L, in THF, 8.45 mL, 21.1 mmol) was added to a solution of B76-01 (2.00 g, 19.2 mmol) in THF (20 mL) at 0 °C, and the mixture was stirred at 20 °C for 2 hours. The reaction was quenched by adding Na₂SO₄·10H₂O (5.00 g) at 0 °C, followed by filtration and concentration under reduced pressure to obtain B76-02 (1.00 g, 57.8% yield). ¹H NMR (400 MHz, CDCl₃) δ 3.82 (d, J = 22.0 Hz, 2H), 2.17 (s, 1H), 1.15–1.01 (m, J = 22.0 Hz, 2H), 1.15–1.01 (m, J = 22.0 Hz, 2H), 1.15–1.01 (m, J = 22.0 Hz, 2H), 1.15–1.01 (m, J = 22.0 Hz, 2H), 1.15–1.01 (m, J = 22.0 Hz, 2H), 1.15–1.01 (m, J = 22.0 Hz, 2H), 1.15–1.01 (m, J = 22.0 Hz, 2H), 1.10–1.01 (m, J = 22.0 Hz, 2H), 1.10–1.01 (m, J = 22.0 Hz, 1 ...2H), 0.74–0.63 (m, 2H).

[0772] TEA (4.41 mL, 31.8 mmol) was added to a solution of B76-02 (955 mg, 10.599 mmol) in DCM (20 mL), followed by the slow addition of methanesulfonic anhydride (2.77 g, 15.9 mmol). The mixture was stirred at 20 °C for 2 hours. The resulting mixture was quenched with H2O (50 mL) and extracted with DCM (50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give B76-03 (1.70 g, 95.4% yield). ¹H NMR (400MHz, CDCl₃) δ 4.40 (d, J=22.0 Hz, 2H), 3.03 (s, 3H), 1.27–1.16 (m, 2H), 0.89–0.81 (m, 2H).

[0773] DIPEA (2.74 mL, 16.5 mmol) and KI (589 mg, 3.31 mmol) were added to a solution of B76-04 (800 mg, 3.31 mmol) in DMF (20 mL), followed by B76-03 (668 mg, 3.97 mmol). The mixture was stirred at 80 °C for 16 hours. The reaction was diluted with H₂O (30 mL) and extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine (20 mL 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (elution gradient of 20 to 40% THF / petroleum ether @ 50 mL / min) to give B76 (500 mg, 54.5% yield). LCMS: MS m / z (ESI) [M+H]+=278.2.

[0774] Intermediate B77 Specification 109 / 206 pages 120 CN 121285551 A

[0775]

[0776] Cs2CO3 (5.20 g, 16.1 mmol) and RuPhos Pd G3 (45.2 mg, 0.054 mmol) were added to a solution of B39-01 (1.00 g, 5.37 mmol) and 2-fluoro-1-iodobenzene (1.20 g, 5.37 mmol) in THF (10.0 mL). The reaction mixture was stirred at 80 °C under N2 for 12 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue (SiO₂) was purified by column chromatography.Petroleum ether / THF = 100 / 0-3 / 1) was used to obtain B77-01 (300 mg, 19.9% ​​yield). LCMS: MS m / z (ESI) [M+H]+ = 281.1.

[0777] NaH (114 mg, 2.85 mmol) was slowly added to a solution of B77-01 (200 mg, 0.714 mmol) in DMF (2.00 mL) at 0 °C. After 15 minutes, B77-02a (125 mg, 0.714 mmol) was added at 0 °C. The reaction was then allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue (SiO2, petroleum ether / THF = 100 / 0-4 / 1) was purified by column chromatography to give B77-02 (120 mg, 46.8% yield). LCMS: MS m / z (ESI) [M+H]+ = 360.0.

[0778] HCl / dioxane (4M, 1.0 mL) was added to a solution of B77-02 (120 mg, 0.334 mmol) in dioxane (0.5 mL). The resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to give B77 (100 mg, crude product).

[0779] Intermediate B78

[0780]

[0781] 3-chloro-4-fluorobenzene-1-carboxynitrile (251 mg, 1.61 mmol) and K2CO3 (668 mg, 4.83 mmol) were added to a solution of B39-01 (300 mg, 1.61 mmol) in DMF (5 mL). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to remove DMF. The residue was purified by column chromatography (SiO2, MeOH / DCM = 3 / 100) to give B78-01 (410 mg, 79.1% yield). LCMS: MS m / z (ESI) [M+H]+ = 322.0.

[0782] A solution of B78-01 (410 mg, 1.27 mmol) in HCl / dioxane (4 M, 5 mL) was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give B78-02 (320 mg, 97.3%). LCMS: MS m / z (ESI) [M+1]+ = 222.0.

[0783] A solution of B78-02 (320 mg, 1.24 mmol) in DMF (5 mL) was added with (bromomethyl)cyclopropane (209 mg, 1.55 mmol).The reaction mixture was prepared with 1.07 g (7.75 mmol) of K2CO3 (1.07 g, 7.75 mmol) and 257 mg (1.55 mmol) of potassium iodide. The reaction mixture was stirred at 90 °C for 18 hours. The residue was diluted with 10 mL of H2O and extracted with 20 mL of EtOAc. The combined organic layers were washed with 20 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue (SiO2, DCM / MeOH = 100 / 0-100 / 3) was purified by column chromatography to give B78 (240 mg, 70.2% yield). LCMS: MS m / z (ESI) [M+1]+ = 276.1.

[0784] Intermediate B79

[0785]

[0786] Cs2CO3 (9.40 g, 28.8 mmol), KOAc (0.900 g, 9.61 mmol) and Pd(dppf)Cl2 (0.700 g, 0.961 mmol) were added to a solution of B79-01 (3.50 g, 11.5 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazole (2.00 g, 9.61 mmol) in DMSO (20.0 mL). The reaction mixture was stirred at 80 °C under N2 atmosphere for 1 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL). The combined organic layers were washed with brine (30 mL), dried with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 3 / 1) to give B79-02 (2.20 g, 89.7% yield). LCMS: MS m / z (ESI) [M+H]+ = 254.8.

[0787] B79 was prepared from B79-02 using a method similar to that used in the synthesis of B47. LCMS: MS m / z (ESI) [M+H]+ = 314.9.

[0788] Intermediate B80

[0789]

[0790] The title compound was prepared from 2,4-difluoro-1-iodobenzene using a method similar to that used in the synthesis of B77. LCMS: MS m / z (ESI) [M+H]+=253.2.

[0791] Intermediate B81 Specification 111 / 206 pages 122 CN 121285551 A

[0792]

[0793] The title compound was prepared from (bromomethyl)cyclopropane using a method similar to that described for the synthesis of B77. LCMS: MS m / z (ESI) [M+H]+=235.2.

[0794] Intermediate B82

[0795]

[0796] The title compound was prepared from 2-bromo-1,3-difluorobenzene using a method similar to that described for the synthesis of B77. LCMS: MS m / z (ESI) [M+H]+=253.1;

[0797] Intermediate B83

[0798]

[0799] DIPEA (2.67 mL, 16.1 mmol) and KI (574 mg, 3.23 mmol) were added to a mixture of B76-04 (780 mg, 3.23 mmol) and 1-bromobut-2-yne (429 mg, 3.23 mmol) in DMF (10 mL). The mixture was stirred at 80 °C for 16 hours. The reaction was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (10 mL 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (20 to 50% THF / petroleum ether gradient elution @ 50 mL / min) to give B83 (410 mg, 49.4% yield). LCMS: MS m / z (ESI) [M+H]+=258.2.

[0800] Intermediate B84 Specification 112 / 206 pages 123 CN 121285551 A

[0801]

[0802] The title compound was prepared from (bromomethyl)cyclobutane using a method similar to that described for the synthesis of B47. LCMS: MS m / z (ESI) [M+H]+=274.1.

[0803] Intermediate B85

[0804]

[0805] The title compound was prepared from B76-04 and 1-iodo-2-methylpropane using a method similar to that used in the synthesis of B83. LCMS: MS m / z (ESI) [M+H]+=262.2.

[0806] Intermediate B86

[0807]

[0808] The title compound was prepared from pyrimidine-2-carboxaldehyde using a method similar to that used in the synthesis of B60. LCMS: MS m / z (ESI) [M+H]+=273.2.

[0809] Intermediate B87 Specification 113 / 206 pages 124 CN 121285551 A

[0810]

[0811] The title compound was prepared from 2,3,5-trifluoropyridine using a method similar to that used in the synthesis of B47. LCMS: MS m / z (ESI) [M+H]+=254.3.

[0812] Intermediate B88

[0813]

[0814] The title compound was prepared from 2,3-difluoropyridine using a method similar to that used in the synthesis of B47.LCMS: MS m / z (ESI) [M+H]+=236.1.

[0815] Intermediate B89

[0816]

[0817] The title compound was prepared from 3-chloro-2-fluoropyridine using a method similar to that described for the synthesis of B01. 1H NMR (400 MHz, DMSO‑d6) δ 9.75‑9.38 (m, 2H) , 8.10 (d , J=3.6 Hz, 1H) , 7.78 (d , J=7.6 Hz, 1H) , 6.82 (dd, J=7.6, 4.8 Hz, 1H) , 3.97-3.66 (m, 5H), 2.58 (s, 3H), 2.35-2.24 (m, 1H), 2.23-2.12 (m, 1H).

[0818] Intermediate B90

[0819]

[0820] 2,3-difluoropyridine (180 mg, 1.56 mmol) and DIPEA (0.78 mL, 4.69 mmol) were added to a solution of B58-01 (316 mg, 1.56 mmol) in DMF (5 mL), and the mixture was stirred at 70 °C for 16 hours. The resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give B90-01 (80.0 mg, 79.1% yield). LCMS: MS m / z (ESI) [M+H]+=298.1.

[0821] Imidazole (229 mg, 3.36 mmol) and TBSCl (243 mg, 1.62 mmol) were added to a solution of B90-01 (400 mg, 1.35 mmol) in DMF (4 mL), and the mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (20% THF / petroleum ether elution @ 50 mL / min) to give B90-02 (410 mg, 74.0% yield). LCMS: MS m / z (ESI) [M+H]+=412.2.

[0822] NaH (58.3 mg, 1.46 mmol) was added to a solution of B90-02 (400 mg, 0.972 mmol) in DMF (10 mL) at 0 °C, and the mixture was then subjected to 0 °C.The mixture was stirred at 20 °C for 30 minutes, and then CH3I (414 mg, 2.92 mmol) was added. The mixture was stirred at 20 °C for 16 hours. The resulting mixture was poured into a saturated NH4Cl aqueous solution (20 mL), extracted with ethyl acetate (30 mL), washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (20% THF / petroleum ether gradient elution @ 100 mL / min) to give B90-03 (260 mg, 62.9% yield). LCMS: MS m / z (ESI) [M+H]+=426.3.

[0823] HCl / dioxane (4 mol / L, 5 mL) was added to a solution of B90-03 (240 mg, 0.564 mmol) in MeOH (2 mL), and the mixture was stirred at 20 °C for 3 hours. The mixture was concentrated under reduced pressure to obtain B90 (200 mg, crude product). LCMS: MS m / z (ESI) [M+H]+=326.2.

[0824] Intermediate B91

[0825]

[0826] DIPEA (0.20 mL, 1.23 mmol) was added to a solution of 2,3-difluoropyridine (142 mg, 1.23 mmol) and B59-01 (250 mg, 1.23 mmol) in DMF (4 mL). The mixture was stirred at 70 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with H2O (2 mL), extracted with EtOAc (10 mL), the organic layer was dried with Na2SO4, filtered, and concentrated. The residue (SiO2, petroleum ether / THF = 100 / 0-1 / 1) was purified by column chromatography to obtain B91-01 (340 mg, 92.5% yield). LCMS: MS m / z (ESI) [M+H]+=297.9; 1H NMR (400 MHz, CD3OD) δ 7.83 (dt, J=4.8, 1.2 Hz, 1H) , 7.29 (ddd , J=13.6, 7.6, 1.2 Hz, 1H) , 6.59 (ddd , J= 8.0, 4.8, 3.2 Hz, 1H), 4.23‑4.18 (m, 1H), 4.02‑3.91 (m, 2H), 3.91‑3.83 (m, 1H), 3.58‑3.48 (m, 2H), 1.45 (s, 9H).

[0827] TBSCl (168 mg) was added to a solution of B91-01 (277 mg, 0.932 mmol) in DMF (3 mL).The mixture was stirred at 25°C for 16 hours with imidazole (159 mg, 2.33 mmol) and 1.12 mg (1.12 mmol). The reaction mixture was diluted with H2O (2 mL), extracted with EtOAc (10 mL), the organic layer was dried with Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 100 / 1-90 / 10) to give B91-02 (380 mg, 99.1% yield). LCMS: MS m / z (ESI) [M+H]+ = 412.2.

[0828] NaH (54.2 mg, 1.36 mmol) was added to a solution of B91-02 (372 mg, 0.904 mmol) in DMF (4 mL) at 0°C. The mixture was stirred at 0 °C for 30 min, and then CH3I (384 mg, 2.71 mmol) was slowly added. The mixture was stirred at 20 °C under a N2 atmosphere for 12 h. The reaction mixture was quenched with H2O (3 mL) and extracted with EtOAc (10 mL 3). The combined organic layers were washed with brine (5 mL 3), dried over Na2SO4, filtered, and concentrated. The residue (SiO2, petroleum ether / THF = 100 / 1–10 / 1) was purified by column chromatography (see instructions on page 126 of CN 121285551 A) to give B91-03 (320 mg, 83.2% yield). LCMS: MS m / z (ESI) [M+H]+=426.3; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J=4.4 Hz, 1H), 7.17 (dd, J=12.8, 8.0 Hz, 1H), 6.62-6.52 (m, 1H), 1.48 (s, 9H) , 0.89 (s, 9H), 0.09 (s, 6H).

[0829] HCl / dioxane (4M, 4 mL) was added to a solution of B91-03 (281 mg, 0.660 mmol) in MeOH (2 mL). The mixture was stirred at 25 °C for 4 hours. The reaction mixture was concentrated to give B91 (130 mg, 93.2% yield). LCMS: MS m / z (ESI) [M+H]+=212.0.

[0830] Intermediate B92

[0831]

[0832] K2CO3 (3.7 g, 27.1 mmol) and CH3I (5.8 g, 40.7 mmol) were added to a solution of B92-01 (2 g, 13.6 mmol) in acetone (40 mL) at 0 °C, and the mixture was then heated to 40 °C and stirred for 12 hours. The reaction solution was diluted with H2O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give B92-02 (1.80 g, 82.1% yield). LCMS: MS m / z (ESI) [M+H]+=162.2; 1H NMR (400MHz, CDCl3) δ 7.92 (d, J=2.4 Hz, 1H), 7.06 (dd, J=9.2, 2.4 Hz, 1H), 3.87 (s, 3H).

[0833] BO1-01 (744 mg, 3.71 mmol), RuPhos Pd G3 (129 mg, 0.15 mmol) and Cs2CO3 (2.02 g, 6.19 mmol) were added to a solution of B92-02 (500 mg, 3.09 mmol) in dioxane (10 mL). The reaction was stirred at 100 °C under N2 atmosphere for 12 hours. The reaction mixture was concentrated. The residue was purified by silica gel chromatography (SiO2, petroleum ether / EtOAc = 100 / 0-4 / 1) to give B92-03 (900 mg, 89.4% yield). LCMS: MS m / z (ESI) [M+H]+=326.3; 1H NMR (400MHz, CDCl3) δ 7.70 (d, J=2.4 Hz, 1H), 6.93 (dd, J=13.6, 2.4 Hz, 1H), 5.00-4.62 (m, 1H) , 3.78 (s, 3H), 3.76-3.59 (m, 2H), 3.55-3.45 (m, 2H), 2.83 (s, 3H), 2.18-1.94 (m, 2H), 1.47 (s, 9H).

[0834] A solution of B92-03 (300 mg, 0.922 mmol) in HCl / dioxane (4 M, 8 mL) was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to give crude product B92 (200 mg, 96.3%). LCMS: MS m / z (ESI) [M+H]+=226.2.

[0835] Intermediate B93

[0836] Specification 116 / 206 pages 127 CN 121285551 A

[0837] The title compound was prepared from 5-bromo-1-methylpyridin-2(1H)-one using a method similar to that used in the synthesis of B12.

[0838] Intermediate B94

[0839]

[0840] The title compound was prepared from 4-bromo-1-methylpyridin-2(1H)-one using a method similar to that used in the synthesis of B13. 1H NMR (400 MHz, DMSO‑d 6) δ 9.73‑9.40 (m, 2H), 7.83 (d, J=7.6 Hz, 1H), 6.37‑6.31 (m, 1H), 5.87 (s, 1H), 3.92‑3.84 (m, 1H) , 3.74‑3.67 (m, 1H) , 3.65‑3.58 (m, 2H) , 3.53 (s, 3H) , 3.46‑3.39 (m, 1H) , 2.61‑2.57 (m, 3H) , 2.37‑ 2.27 (m, 2H).

[0841] Intermediate B95

[0842]

[0843] The title compound was prepared from 6-bromo-1-methylpyridin-2(1H)-one using a method similar to that used in the synthesis of B13. LCMS: MS m / z (ESI) [M+H]+=207.9.

[0844] Intermediate B96

[0845]

[0846] The title compound was prepared from 3-bromo-1-methylpyridin-2(1H)-one using a method similar to that used in the synthesis of B13. LCMS: MS m / z (ESI) [M+H]+=207.9.

[0847] Intermediate B97 Specification 117 / 206 pages 128 CN 121285551 A

[0848]

[0849] Pd(dppf)Cl2 (340 mg, 0.464 mmol) and K2CO3 (1.92 g, 13.9 mmol) were added to a mixture of B97-01 (1.50 g, 4.64 mmol) and 4-bromo-2-methylbenzene-1-carboxynitrile (0.910 g, 4.64 mmol) in dioxane (15 mL) and H2O (3 mL). The mixture was stirred at 100 °C under N2 atmosphere for 12 hours. The reaction was filtered, and the filtrate was concentrated to give the residue. The residue was diluted with H2O (20 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product (0 to 5% EtOAc / silica gel) was purified by rapid silica gel chromatography.Elution was performed using an oil-ether gradient (50 mL / min) to give the desired product B97-02 (1.0 g, 68.98% yield). LCMS: MS m / z (ESI) [M-t-Bu+H]+=257.0.

[0850] NaH (115 mg, 4.80 mmol) was added to a mixture of B97-02 (500 mg, 1.60 mmol) in MeCN (5 mL) at 0 °C, and the mixture was stirred at 0 °C for 1 h. Then MeI (341 mg, 2.40 mmol) was added, and the mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (SiO2, 0 to 6% EtOAc / petroleum ether gradient elution @ 40 mL / min) to give the desired product B97-03 (500 mg, 95.7% yield). LCMS:MS m / z (ESI) [M‑t‑Bu+H]+= 271.0; 1H NMR (400 MHz, DMSO‑d 6) δ 7.69 (d, J=8.4 Hz, 1H), 7.50 (s, 1H), 7.41 (dd, J=8.0, 1,2 Hz, 1H) , 6.34‑6.26 (m, 1H) , 4.20‑3.94 (m, 1H) , 2.72 (s, 3H) , 2.62‑2.52 (m, 2H) , 2.47 (s, 3H) , 2.38‑2.15 (m, 2H) , 1.89‑1.70 (m, 2H) , 1.41 (s, 9H).

[0851] A mixture of B97-03 (450 mg, 1.379 mmol) in HCl / dioxane (4M, 5 mL) was stirred at 25 °C for 1 hour. The solvent was then removed under reduced pressure to give B97 (390 mg, crude). LCMS:MS m / z (ESI) [M+1]+=227.1.

[0852] Intermediate B98

[0853]

[0854] The title compound was prepared from 4-bromo-1-methyl-1H-pyrazole using a method similar to that used in the synthesis of B97. LCMS:MS m / z (ESI) [M+1]+=192.1.

[0855] Intermediate B99

[0856]

[0857] The title compound was prepared from 4-bromobenzyl nitrile and iodoethane using a method similar to that used in the synthesis of B97. Specification page 118 / 206, page 129, CN 121285551 A

[0858] Intermediate B100

[0859]

[0860] 60% NaH (0.370 g, 15.5 mmol) was slowly added to a mixture of B97-01 (1 g, 3.10 mmol) in THF (20 mL) at 0 °C, and the mixture was stirred at 0 °C for 10 min. Then MeI (0.880 g, 6.19 mmol) was added, and the mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (0 to 7% EtOAc / petroleum ether gradient elution @ 60 mL / min) to give the desired product B100-01 (580 mg, 55.6% yield). 1H NMR: (400 MHz, DMSO‑d 6) δ 6 .47‑6 .35 (m , 1H) , 4 .21‑3 .76 (m , 1H) , 2 .66 (s , 3H) , 2.29‑2.00 (m, 4H) , 1.62‑1.52 (m, 2H), 1.39 (s, 9H), 1.20 (s, 12H).

[0861] K2CO3 (713 mg, 5.16 mmol) and Pd(PPh3)4 (199 mg, 0.172 mmol) were added to a mixture of B100-01 (580 mg, 1.72 mmol) and 2-bromo-1,3-thiazolyl-4-carboxynitrile (325 mg, 1.72 mmol) in dioxane (10 mL) and H2O (2 mL). The mixture was stirred at 100 °C under a N2 atmosphere for 12 hours. The reaction mixture was filtered and concentrated. The residue was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by rapid silica gel chromatography (0 to 10% EtOAc / petroleum ether gradient elution @ 50 mL / min) to obtain the desired product B100-02 (210 mg, 38.2%). LCMS: MS m / z (ESI) [M+1]+= 220.1; 1H NMR: (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 6.83–6.67 (m, 1H), 4.17–3.95 (m, 1H), 2.71 (s, 3H), 2.62–2.51 (m, 2H), 2.44–2.20 (m, 2H), 1.90–1.90 (m, 2H), 1.40 (s, 1H).9H).

[0862] The compound of B100-02 (210 mg, 0.657 mmol) was dissolved in 4M HCl / dioxane (2 mL), and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to give B100 (140 mg, 97.1%, HCl salt).

[0863] Intermediate B101

[0864]

[0865] B101-01 (3.10 g, 38.2 mmol), Na2CO3 (10.1 g, 95.5 mmol), XPHOS (1.50 g, 3.19 mmol), t-Bu3PBF4 (1.80 g, 6.37 mmol) and Pd(PPh3)2Cl2 (1.20 g, 1.59 mmol) were added to a solution of bromobenzene (3.36 mL, 31.8 mmol) in DMSO (50 mL). The mixture was stirred at 100 °C under a N2 atmosphere for 16 hours. The reaction mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (200 mL). The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (elution gradient of 0 to 40% THF / petroleum ether @ 100 mL / min) to give B101-02 (1.50 g, 29.8% yield).

[0866] Cerium trichloroisocyanurate (III) (2.03 g, 8.217 mmol) and NaBH4 (373 mg, 9.86 mmol) were added to a solution of B101-02 (1.30 g, 8.22 mmol) in ethanol (20 mL) at 0 °C, and the mixture was stirred at 20 °C for 3 hours. The mixture was quenched by adding 1 mol / L HCl (3 mL) at 0 °C, then diluted with H2O (20 mL), and extracted with ethyl ethyl ester (20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give B101-03 (1.30 g, crude). LCMS: MS m / z (ESI) [M+H]+=161.2.

[0867] TEA (3.12 mL, 22.5 mmol) was added to a solution of B101-03 (1.20 g, 7.49 mmol) in DCM (20 mL), followed by slow addition of methanesulfonic anhydride (1.96 g, 11.2 mmol). The mixture was stirred at 20 °C for 2 hours. The mixture was diluted with 20 mL of H₂O and extracted with 20 mL of DCM. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give B₁₀₄ (1.70 mL).

[0868] A solution of B101-04 (1.60 g, 6.71 mmol) in methylamine (15.0 g, 145 mmol, 30% in ethanol) was stirred at 20 °C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (60 to 80% THF / PE elution @ 20 mL / min) to give B101 (300 mg, 33.3% yield). LCMS: MS m / z (ESI) [M +H]+=174.2.

[0869] Intermediate B102

[0870]

[0871] Br2 (4.62 mL, 84.1 mmol) was added to a solution of PPh3 (23.5 g, 89.7 mmol) in DCM (200 mL) at 0 °C, and the reaction mixture was stirred at the same temperature for 15 min. TEA (13.6 mL, 98.0 mmol) and B102-01 (8.00 g, 81.5 mmol) were added to DCM (100 mL). The mixture was stirred at 20 °C for 16 hours. The reaction was concentrated. The residue was purified by rapid silica gel chromatography (30% THF / petroleum ether elution @ 100 mL / min) to give B102-02 (1.50 g, 11.4% yield). ¹H NMR (400 MHz, DMSO-d6) δ 6.58 (t, J = 1.6 Hz, 1H), 3.02–2.94 (m, 2H), 2.50–2.46 (m, 2H).

[0872] To a solution of B102-02 (2.00 g, 12.4 mmol) in dioxane (20 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentane (3.80 g, 14.9 mmol), KOAc (2.40 g, 24.8 mmol) and Pd(dppf)Cl2 (0.90 g, 1.24 mmol) were added. The reaction was stirred at 80 °C for 16 hours. The reaction was filtered and concentrated under reduced pressure to give B102-03 (2.56 g, crude product).

[0873] K3PO4 (5.22 g, 24.6 mmol), B102-O3 (2.56 g, 12.3 mmol), and Pd(dppf)Cl2 (899 mg, 1.23 mmol) were added to a solution of 2-bromo-3-fluoropyridine (2.15 g, 12.3 mmol) in dioxane (40 mL) and H2O (10 mL). The reaction was stirred at 80 °C under a N2 atmosphere for 16 hours. The resulting mixture was diluted with water (50 mL) and thiamethoxam (50 mL) with ethyl acetate (50 mL).3) Extraction. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (20% THF / petroleum ether elution @ 50 mL / min) to give B102-04 (3.00 g, 96.4% yield). LCMS: MS m / z (ESI) [M+H]+=178.1.

[0874] At 0 °C, cerium trichloroethylene (C3) (4.17 g, 16.9 mmol) was added to a solution of B102-04 (3.00 g, 16.9 mmol) in ethanol (50 mL), followed by NaBH4 (768 mg, 20.3 mmol). The mixture was stirred at 20 °C for 3 hours. The reaction mixture was poured into an ice-saturated aqueous solution of NH4Cl (100 mL) and extracted with ethyl acetate (200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by rapid silica gel chromatography (30% THF / petroleum ether elution @ 100 mL / min) to give B102-05 (1.50 g, 49.4% yield). LCMS: MS m / z (ESI) [M+H]+=180.1.

[0875] DPPA (1.84 g, 6.70 mmol) and DBU (1.02 mg, 6.70 mmol) were added to a solution of B102-05 (1.00 g, 5.58 mmol) in THF (20 mL), and the mixture was stirred at 20 °C under a N2 atmosphere for 16 hours. The mixture was diluted with saturated NH4Cl aqueous solution (100 mL) and extracted with ethyl acetate (100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (30% THF / petroleum ether elution @ 100 mL / min) to give B102-06 (1.08 g, 94.8% yield). LCMS: MS m / z (ESI) [M+H]+=205.1.

[0876] PPh3 (1.41 mg, 5.39 mmol) was added to a solution of B102-06 (1.00 mg, 4.90 mmol) in THF (20 mL) and H2O (2 mL). The mixture was stirred at 70 °C under N2 atmosphere for 1 hour. The mixture was cooled to 20 °C, and (Boc)2O (2.25 mL, 9.79 mmol) and TEA (2.04 mL, 14.7 mmol) were added. The mixture was stirred at 50 °C.Stirred at ℃ for 0.5 hours. The mixture was concentrated under pressure. The residue was purified by rapid silica gel chromatography (20% THF / petroleum ether elution @ 100 mL / min) to give B102-07 (700 mg, 51.4% yield). LCMS: MS m / z (ESI) [M+H]+ = 279.2.

[0877] NaH (201 mg, 5.03 mmol) was added to a solution of B102-07 (700 mg, 2.52 mmol) in DMF (14 mL) at 0 ℃, and the mixture was stirred at 0 ℃ for 30 minutes. CH3I (1.07 mg, 7.55 mmol) was added. The mixture was stirred at 30 ℃ for 2 hours. The reaction mixture was poured into a saturated NH4Cl aqueous solution (30 mL) and extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine (10 mL 3), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give B102-08 (700 mg, 95.2% yield). LCMS: MS m / z (ESI) [M+H]+=293.1.

[0878] The mixture of B102-08 (700 mg, 2.39 mmol) in HCl / dioxane (4 mol / L, 10 mL) was stirred at 20 °C for 1 hour. The mixture was concentrated under reduced pressure to give B102 (540 mg, crude product). LCMS: MS m / z (ESI) [M+ H]+=193.1.

[0879] Intermediate B103 Specification 121 / 206 pages 132 CN 121285551 A

[0880]

[0881] DIPEA (8.87 mL, 53.524 mmol) was added to a solution of B103-01 (5.00 g, 44.603 mmol) in DCM (150 mL), and then trifluoromethanesulfonic anhydride (13.8 g, 49.063 mmol) was added dropwise at -70 °C. The mixture was stirred at -70 °C for 2 hours. The resulting mixture was quenched with H2O (200 mL) and extracted with DCM (200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0 to 10% THF / petroleum ether gradient elution @ 100 mL / min) to give B103-02 (5.40 g, 49.6% yield). ¹H NMR (400 MHz, CDCl3) δ 2.96–2.83 (m, 2H), 2.70–2.58 (m, 2H), 1.77 (t, J = 2.0 Hz, 3H).

[0882] B103 was prepared from B103-O2 using a method similar to that used for the synthesis of B102. LCMS: MS m / z (ESI) [M+H]+=207.1; 1H NMR (400MHz, DMSO‑d 6) δ 9.65‑9.15 (m, 2H) , 8.58‑8.48 (m, 1H) , 7.93‑7.82 (m, 1H) , 7.58‑7.48 (m, 1H) , 4.39‑4.27 (m, 1H) , 2.95‑2.83 (m, 1H) , 2.82‑2.72 (m, 1H) , 2.50‑2.46 (m, 3H) , 2.38‑2.25 (m, 1H) , 2.09‑1.98 (m, 1H) , 1.84 (s, 3H).

[0883] Intermediate B104 Specification 122 / 206 pages 133 CN 121285551 A

[0884]

[0885] 2-methylpropyl-2-carbamate (2.90 g, 24.4 mmol) and bismuth nitrate (11.5 g, 29.2 mmol) were added to a solution of B101-01 (2.00 g, 24.4 mmol) in DCM (60 mL), and the reaction was stirred at 25 °C for 5 hours. The reaction suspension was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 10 / 1-3 / 1) to obtain B104-01 (700 mg, 14.4%). 1H NMR (400MHz, CDCl3) δ 4.63 (brs, 1H) , 4.22 (brs, 1H) , 2.68‑2.55 (m, 1H) , 2.43‑2.29 (m, 2H) , 2.27‑2.17 (m, 1H) , 2.16‑2.06 (m, 1H), 1.88‑1.79 (m, 1H), 1.44 (s, 9H). Instructions for Use, Page 123 / 206, 134, CN 121285551 A

[0886] 2-(methoxymethyl)ethylene oxide-1-onium (7.02 mL, 7.03 mmol) was added to a mixture of B104-01 (700 mg, 3.51 mmol) in THF (7 mL) at -78 °C, and stirred for 30 minutes. Then, N-[dioxo(trifluoromethyl)-λ6-thioalkyl]-1,1,1-trifluoro-N-phenylmethanesulfonamide (2.13 g, 5.97 mmol) was slowly added. The reaction was stirred at 0 °C under a N2 atmosphere for 10 minutes. The reaction suspension was quenched with water (10 mL) and treated with EtOAc (10 mL).3) Extraction. The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 10 / 1-3 / 1) to give a mixture of B104-02a & B104-02b (1.00 g, 85.9% yield).

[0887] To a solution of B104-02a & B104-02b (1.00 g, 3.02 mmol) in dioxane (10 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentane (920 mg, 3.62 mmol), Pd(dppf)Cl2 (221 mg, 0.302 mmol), and KOAc (592.2 mg, 6.04 mmol) were added. The reaction suspension was then stirred at 80 °C under a N2 atmosphere for 14 hours. The reaction suspension was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 10 / 1-1 / 1) to give a mixture of B104-03 & B102-07 (730 mg, 78.2% yield).

[0888] 2-bromo-3-fluoropyridine (350 mg, 1.99 mmol), K3PO4 (844.4 mg, 3.98 mmol) and Pd(dppf)Cl2 (146 mg, 0.199 mmol) were added to a solution of B104-03a & B104-03b (738 mg, 2.39 mmol) in dioxane (6 mL) and H2O (1 mL), and the reaction suspension was stirred at 90 °C for 2 hours. The reaction suspension was diluted with water (5 mL) and extracted with EtOAc (4 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 10 / 1-1 / 1) to give a mixture of B104-04 & B102-07 (370 mg, 66.9% yield). LCMS: MS m / z (ESI) [M+H]+ = 279.2.

[0889] NaH (160 mg, 3.99 mmol) was added to a solution of B104-04 & B102-07 (370 mg, 1.33 mmol) in DMF (3 mL), and the reaction was stirred at 0 °C for 0 min. CH3I (566 mg, 3.99 mmol) was added to the mixture, and the mixture was stirred at 25 °C for 2 h. The reaction suspension was quenched with water (5 mL), and EtOAc (5 mL) was used.3) Extraction. The combined organic layers were washed with brine (2 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a mixture of B104-05 & B102-08 (350 mg, 90.0% yield). LCMS: MS m / z (ESI) [M+H]+=293.2.

[0890] The solution of B104-05 & B102-08 (350 mg, 1.20 mmol) in HCl / dioxane (4M, 2.5 mL) was stirred at 25°C for 1 hour. The reaction suspension was concentrated under reduced pressure to give a crude mixture of B104 & B102 (273 mg, crude product), which was used directly in the next step. LCMS: MS m / z (ESI) [M+H]+=193.3.

[0891] Intermediate B105

[0892]

[0893] Cs2CO3 (2.30 g, 7.07 mmol) and Pd-PEPPSI-IheptCl (229 mg, 0.236 mmol) were added to a mixture of B01-01 (567 mg, 2.83 mmol) and 6-bromo-3-methylbenzo[d]isoxazole (500 mg, 2.36 mmol) in dioxane (10 mL). The mixture was stirred at 100 °C under N2 atmosphere for 18 hours. The resulting mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by rapid silica gel chromatography (0 to 24% THF / petroleum ether gradient elution @ 50 mL / min) to give B105-01 (400 mg, 51.2% yield). LCMS: MS m / z (ESI) [M+H]+= 332.2; 1H NMR (400 MHz, DMSO‑d 6) δ 7.55 (d, J=8.4 Hz, 1H) , 6.69 (dd, J=8.8, 2.0 Hz, 1H) , 6.61 (d , J=2.0 Hz, 1H) , 4.87‑4.66 (m, 1H) , 3.52‑3.42 (m, 2H) , 3.32‑ 3.23 (m, 2H) , 2.76 (s, 3H) , 2.43 (s, 3H) , 2.21‑2.06 (m, 2H) , 1.43 (s, 9H).

[0894] A mixture of B105-01 (100 mg, 0.302 mmol) in 4M HCl / dioxane (1 mL) was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure to obtain B105. LCMS: MS m / z (ESI)[M+H]+=232.1.

[0895] Intermediate B106

[0896]

[0897] The title compound was prepared from B01-01 and 4-fluoro-2-methoxybenzyl nitrile using a method similar to that described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H]+=232 .2; 1H NMR: (400 MHz, DMSO‑d 6) δ 9 .50 (brs, 2H) , 7.42 (d , J=8.8 Hz, 1H) , 6.23 (dd , J=8.4, 1.6 Hz, 1H) , 6.18 (d, J= 1.6 Hz, 1H), 3.88 (s, 3H), 3.93-3.83 (m, 1H), 3.70-3.63 (m, 1H), 3.62-3.50 (m, 2H), 3.44-3.32 (m, 1H), 2.60(t, J = 5.2 Hz, 3H), 2.41–2.30 (m, 1H), 2.29–2.18 (m, 1H).

[0898] Intermediate B107

[0899]

[0900] The title compound was prepared from B107-01 and 5-fluoropyridine nitrile using a method similar to that used in the synthesis of B01. LCMS: MS m / z (ESI) [M+H]+ = 217.1.

[0901] Intermediate B108 Specification 125 / 206 pages 136 CN 121285551 A

[0902]

[0903] The title compound was prepared from B107-01 and 6-fluoronicotinamide using a method similar to that used in the synthesis of B01. LCMS: MS m / z (ESI) [M+H]+=217.2.

[0904] Intermediate B109

[0905]

[0906] The title compound was prepared from BO1-01 and 4-bromo-2-(fluoromethoxy)benzyl nitrile using a method similar to that used in the synthesis of B13. LCMS: MS m / z (ESI) [M+H]+=250.1.

[0907] Intermediate B110

[0908]

[0909] The title compound was prepared from BO1-01 and 5-bromo-2-methylisodihydroindole-1,3-dione using a method similar to that used in the synthesis of B13. LCMS: MS m / z (ESI) [M+H]+=260.1; 1H NMR (400 MHz, CD3OD) δ 7.67 (d, J=8.4 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 6.89 (dd, J=8.4,2.4 Hz, 1H) , 4.09‑3.98 (m, 1H) , 3.87‑3.78 (m, 1H) , 3.74‑3.64 (m, 2H) , 3.61‑3.52 (m, 1H) , 3.07 (s, 3H) , 2.82 (s, 3H) , 2.64-2.51 (m, 1H), 2.38-2.26 (m, 1H).

[0910] Intermediate B111 Specification 126 / 206 pages 137 CN 121285551 A

[0911]

[0912] NBS (1.5 g, 8.43 mmol) was added to a solution of B111-01 (1.14 g, 8.43 mmol) in DMF (20 mL) at 0 °C. The mixture was stirred at 25 °C for 2.5 hours. The mixture was diluted with water (30 mL), the solid was filtered, and the mixture was concentrated under vacuum to give B111-02 (1.6 g, 89% yield). LCMS: MS m / z (ESI) [M+H]+=213.9; 1H NMR (400 MHz, CDCl3) δ ...

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof: Formula (I) wherein: Ring A is a 4- to 7-membered cycloalkyl or a 4- to 7-membered heterocycloalkyl; R 4 each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, C 1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 4a ; or two R on the same atom 4 together form oxo; or two R on the same atom 4 together with the atom to which they are attached form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one or more R 4b substituents; R 4a each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, C 1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or two R on the same atom 4a together form oxo; R 4b each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, C 1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or two R on the same atom 4b together form oxo; n is 1, 2, 3, 4, 5, or 6; R 5 -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b -C(=O)R a -C(=O)OR b -C(=O)NR c R d C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, C 1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 5a ; R 5a each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, C 1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or two R on the same atom 5a together form oxo; W is N or CR W ; R W is hydrogen, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, C 1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R U is N or CR U ; R U is hydrogen, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, C 1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R T is N or CR T ; R T is hydrogen, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, C 1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R X is C and Y is C; or X is C and Y is N; or X is N and Y is C; Z 1 is O, S, N, NR 1a , CR 1b or C(R 1c )2; Z 2 is O, S, N, NR 2a , CR 2b or C(R 2c )2; Z 3 is O, S, N, NR 3a , CR 3b or C(R 3c )2; R 1a , R 2a , and R 3a are each independently hydrogen, C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, C 1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R 1b , R 2b , and R 3b are each independently hydrogen, halogen, -CN, -NO2, -OH, -OR a , -SF5, -SH, -SR a , -NR c R d , C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, C 1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R 1c each independently hydrogen, halogen, -CN, -N02, -OH, -OR a , -SF5, -SH, -SR a , -NR c R d , C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, C 1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or two R 1c together form oxo; R 2c each independently hydrogen, halogen, -CN, -N02, -OH, -OR a , -SF5, -SH, -SR a , -NR c R d , C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, C 1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or two R 2c together form oxo; R 3c each independently hydrogen, halogen, -CN, -NO2, -OH, -OR a , -SF5, -SH, -SR a , -NR c R d , C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, C 1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or two R 3c together form oxo; R a each independently C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, C 1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R b each independently hydrogen, C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, C 1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R c and R d each independently is hydrogen, C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, C 1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R c and R d with the atom to which they are attached to form a heterocycloalkyl group, which is optionally substituted with one or more R; L is absent or C optionally substituted with one or more R 1- C4alkylene; and each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C 1- C3alkyl, -S(=O)2C 1- C3alkyl, -S(=O)2NH2, -S(=O)2NHC 1- C3alkyl, -S(=O)2N(C 1- C3alkyl)2, -S(=O)(=NC 1- C3alkyl)(C 1- C3alkyl), -NH2, -NHC 1- C3alkyl, -N(C 1- C3alkyl)2, -N=S(=O)(C 1- C3alkyl)2, -O-C 1- C4alkylene-OH, -O-C 1- C4alkylene-NH2, -C(=O)C 1- C3alkyl, -C(=O)OH, -C(=O)OC 1- C3alkyl, -C(=O)NH2, -C(=O)NHC 1- C3alkyl, -C(=O)N(C 1- C3alkyl)2, -P(=O)(C 1- C3alkyl)2, C 1- C3alkyl, C 1- C3alkoxy, C 1- C3haloalkyl, C 1- C3haloalkoxy, C 1- C3hydroxyalkyl, C 1- C3aminoalkyl, C 1- C3heteroalkyl, C3-C6cycloalkyl or 3- to 6-membered heterocycloalkyl; or two R on the same atom form an oxo.

2. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (I) has Formula (la): Formula (la) wherein: Ring B is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 6 each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, C 1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or two R on the same atom 6 together form oxo; m is 0, 1, 2, 3, 4, 5, or 6; R 7 each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, C 1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or two R on the same atom 7 together form oxo; p is 0, 1, 2, 3, 4, or 5; and L is absent or C optionally substituted with one or more R 1- C4alkylene.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 6 each independently is halogen, -CN, -NO2, -OH, -OR a , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -NR c R d , -C(=O)R a , -C(=O)OR b , C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, C 1- C6heteroalkyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.

4. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the ring is .

5. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein is .

6. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein is or .

7. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein is .

8. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (I) has Formula (lb): Formula (lb) wherein: Ring C is a cycloalkyl or heterocycloalkyl; R 6 each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, C 1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or two R on the same atom 6 together form oxo; m is 0, 1, 2, 3, 4, 5, or 6; R 7 each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b )2, C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, C 1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or two R on the same atom 7 together form oxo; q is 0, 1, 2, 3, or 4.

9. The compound of any one of claims 1-8 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is a 4- to 6-membered cycloalkyl.

10. The compound of claim 9 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is a 4- to 6-membered fully saturated cycloalkyl.

11. The compound of claim 9 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is a 4- to 6-membered partially saturated cycloalkyl.

12. The compound of claim 11 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is 、 or .

13. The compound of claim 11, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein is or .

14. The compound of any one of claims 1-8 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is a 4- to 6-membered heterocycloalkyl.

15. The compound of claim 14 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is a 4- to 6-membered fully saturated heterocycloalkyl.

16. The compound of claim 15, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is 、 、 or .

17. The compound of claim 15, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein is or .

18. The compound of claim 14 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is a 4- to 6-membered partially saturated heterocycloalkyl.

19. The compound of any one of claims 2-18, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 7 each independently is halogen, -CN, -NO2, -OH, -OR a , -SF5, -SH, -SR a , -NR c R d , C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, or C 1- C6heteroalkyl.

20. The compound of any one of claims 2-18, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein two R 7 together on the same atom form oxo.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 is C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, C 1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 5a substituents.

22. The compound of claim 21 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L is a bond or -CH2-.

23. The compound of claim 21, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 is CH3, CHF2, CF3, CH2CH3, CH2CH(CH3)2, CH2CHF2, CH2CF3, or .

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5a each independently is halogen, -CN, -NO2, -OH, -OR a , -SF5, -SH, -C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, or C 1- C6heteroalkyl; wherein said alkyl is independently optionally substituted with one or more R.

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein W is CR W .

26. The compound of claim 25, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R W is hydrogen, halogen, -CN, -N02, -OH, -OR a , -SF5, -SH, -SR a , -NR c R d , C 1- C6alkyl, C 1- C6haloalkyl, C 1- C6hydroxyalkyl, C 1- C6aminoalkyl, or C 1- C6heteroalkyl; wherein said alkyl is optionally substituted with one or more R.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein U is CR U .

28. The compound of claim 27, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R U is hydrogen, halogen, -CN, -N02, -OH, -OR a , -SF5, -SH, -SR a , -NR c R d , C 1- C6 alkyl, C 1- C6 haloalkyl, C 1- C6 hydroxyalkyl, C 1- C6 aminoalkyl, or C 1- C6 heteroalkyl; wherein the alkyl is optionally substituted with one or more R.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein T is CR T .

30. The compound of claim 29, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R T is hydrogen, halogen, -C 1- C3alkyl, C 1- C3haloalkyl, or C2-C3alkynyl.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein is .

32. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein is .

33. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein is .

34. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein is .

35. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from Table 1 and Table 2.

36. A pharmaceutical composition comprising a compound of any one of claims 1-35 or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier or excipient.

37. A method of treating a disease or disorder, the method comprising administering to an individual in need thereof a compound of any one of claims 1-35 or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutical composition of claim 36, wherein the disease or disorder is associated with overexpression of PRMT5.

38. The method of claim 37, wherein the disease or disorder is a cancer.

39. A method of treating a cancer, the method comprising administering to an individual in need thereof a compound of any one of claims 1-35 or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutical composition of claim 37.

40. The method of any one of claims 38 or 39, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, uterine cancer, cholangiocarcinoma, gastric cancer, bladder cancer, cervical cancer, testicular germ cell cancer, and non-small cell lung cancer and multiple myeloma, diffuse large B-cell lymphoma, rhabdomyosarcoma, and cutaneous squamous cell carcinoma.