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WO2025195464A1 - Composé d'isoindoline substitué, procédé de préparation, composition pharmaceutique et utilisation - Google Patents

Composé d'isoindoline substitué, procédé de préparation, composition pharmaceutique et utilisation

Info

Publication number
WO2025195464A1
WO2025195464A1 PCT/CN2025/083791 CN2025083791W WO2025195464A1 WO 2025195464 A1 WO2025195464 A1 WO 2025195464A1 CN 2025083791 W CN2025083791 W CN 2025083791W WO 2025195464 A1 WO2025195464 A1 WO 2025195464A1
Authority
WO
WIPO (PCT)
Prior art keywords
independently
alkyl
ring
general formula
alkoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/083791
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English (en)
Chinese (zh)
Inventor
戈传生
赵立志
王娟娟
郭瑛
野国中
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Gdac Biotechnology Ltd
Original Assignee
Shanghai Gdac Biotechnology Ltd
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Filing date
Publication date
Application filed by Shanghai Gdac Biotechnology Ltd filed Critical Shanghai Gdac Biotechnology Ltd
Publication of WO2025195464A1 publication Critical patent/WO2025195464A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • Cereblon is the substrate recognition subunit of the CRL4- CRBN E3 ubiquitin ligase complex and is involved in the selective ubiquitination of specific proteins.
  • the underlying mechanism is that the E3 ubiquitin ligase recognizes and binds to specific target proteins, then transfers ubiquitin molecules to these proteins, marking them for proteasomal degradation.
  • Immunomodulators bind to CRBN, leading to degradation of pathogenic proteins by the proteasome (UPS), thereby achieving therapeutic efficacy.
  • IKZF1 and IKZF3 are key transcription factors in multiple myeloma.
  • a single amino acid substitution in IKZF3 renders it resistant to lenalidomide-like immunomodulatory degradation and resistant to lenalidomide-induced cell growth inhibition.
  • lenalidomide-induced IL2 production in T cells is due to the depletion of IKZF1 and IKZF3.
  • Thalidomide and lenalidomide also have other indications, particularly lenalidomide, which can be used to treat myelodysplastic syndrome (MDS).
  • MDS myelodysplastic syndrome
  • the adipic imide moiety of all immunomodulatory drugs (IMiDs) binds to the hydrophobic pocket defined by the three tryptophan residues in CRBN, while the phthalimide/isoindole ring is exposed to the solvent and modifies the molecular surface of CRBN, thereby regulating substrate recognition. Therefore, different modifications of immunomodulatory drugs (IMiDs) may result in different degradation effects.
  • WO2019014100 discloses a novel structure of a lenalidomide-type immunomodulator.
  • the present invention provides a substituted isocyanate compound, a preparation method, a pharmaceutical composition, and its application.
  • the substituted isocyanate compound of the present invention can bind to Cereblon to specifically target and regulate various tumor-related proteins, thereby effectively treating Cancer and other related diseases.
  • the present invention provides an isocyanate compound represented by general formula (XI), its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof.
  • XI isocyanate compound represented by general formula (XI), its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof.
  • ml is 0, 1, 2 or 3
  • m3 is 0, 1, 2 or 3
  • m4 is 0 or 1;
  • R° is H, D or G-4 alkyl
  • R% RD and RU are independently D or H; each R? is the same or different and is independently D, F, Cl, Br, I, CN, C "4 alkyl or C “4 alkoxy, the C "4 alkyl and the C1-4 alkoxy are optionally substituted by one or more Ria; each Ria is independently D, F, Cl, Br or I;
  • X51 , X52 and X53 are independently O, Se or S;
  • X2 is NRX4b, O, Se or S; or, Xi and X2 together with the atoms to which they are connected form a benzene ring;
  • X3 is CR4aR4b; R4a and R4b are the same or different and are each independently H, D, F, Cl, Br, I, CN, C1-4 alkyl or C1-4 alkoxy, wherein the C1-4 alkyl and C1-4 alkoxy are optionally substituted with one or more Rial; each Rial is independently D, F, Cl, Br or I; wherein ring A is connected to X3; m2 is 0, 1, 2 or 3; each R 2 is the same or different and is independently D, F, Cl, Br, I, CN, COOR 2 " (or a choric acid isostere, for example
  • the C1-4 alkyl group and the C1-4 alkoxy group are optionally substituted by one or more Ria2 groups; each R1-32 group is independently D, F, Cl, Br, I, C1-4 alkyl group, C1-4 alkoxy group, aryl group, hydroxyl group or amino group; R2al group is independently H, D, C1-4 alkyl group or C
  • RX4b, RX4b2, RX4C1, and RX4c2 are independently H, D, OH, or Cl-4 alkyl; the Cl-4 alkyl is optionally substituted with one or more D, F, Cl, Br, or I; RX4C3 is independently C1-4 alkylene;
  • RX4al is -L1-R5 or -L11-RX-L12-RY;
  • R5a and R5b are independently H, CM alkyl, or .
  • each R51 is independently NIRSalR5 ⁇ ), SH, OH, C1-6 alkoxy, C1-6 alkyl, hydroxyC1-4 alkyl- or aminoC1-4 alkyl-; wherein, C1-4 alkyl residue, C1-4 alkoxy residue (Boc), Cbz, Fmoc or trifluoroacetyl; the G-4 alkyl, 3-6 membered heterocyclic ring, partially saturated 3-6 membered heterocyclic ring, C3-6 carbocyclic ring substituted with one or more R51 and partially saturated C3-6 carbocyclic ring substituted with one or more R51 are optionally substituted with one or more D, F, Cl, Br or I; In rings Bl, B2, B3 and B5, each Z]
  • each Ra, Rb, RC, Rd, Ra] Rb ⁇ RC, Rd] Re and Rf are the same or different and are independently H, D, F, Cl,
  • each R must independently be D, F, Cl, Br or I; or, (in ring B2) Ra and one of Rc and one of Rd and the carbon atom to which they are attached form a 3- to 6-membered ring; said 3- to 6-membered ring is optionally selected from D, F, Cl, Br, substituted, when there are multiple substituents, the substituents are the same or different;
  • Ring E is a 5-6 membered heterocyclic ring, a partially saturated 5-6 membered heterocyclic ring, a C3-6 carbocyclic ring substituted with one or more R52, or a partially saturated C3-6 carbocyclic ring substituted with one or more R52 ; the heteroatoms in the 5-6 membered heterocyclic ring are selected from N and O, and the number of heteroatoms is 1 or 2;
  • N'J body such as CONHOH, SOW, ⁇ '. ), C'-1, C'-2, C'-3 oxy, C'-4 amino, C'-6 cycloalkyl or
  • a Kl xR 3a crystal wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino and C3-6 cycloalkyl are optionally substituted by one or more R 3 .
  • Each R3C is independently D, F, Cl, Br or I;
  • R?a and R3b are the same or different and are independently H, D, C-4 alkyl, C3-6 cycloalkyl, hydroxyC1-4 alkyl- or aminoC1-4 alkyl-; wherein the end represents connection to the C ring;
  • the C1-4 alkyl and C3-6 cycloalkyl are optionally substituted by one or more D, F, Cl, Br or I;
  • each R4 is the same or different and is independently R6-L3-L2-, R7 - L31 - L21- or R71-L22-;
  • L2, L21 and L22 are independently a linker or a C1-4 alkylene group; the C1-4 alkylene group is optionally substituted with one or more D, F, Cl, Br or I;
  • RX4al is L11-RX-L12-RY.
  • the general formula (XI) is represented by the general formula X: ml is 0, 1, 2 or 3; m3 is 0, 1, 2 or 3; m4 is 0 or 1; R° is H, D or C1-4 alkyl; each R? is the same or different and independently is D, F, Cl, Br, I, CN, C1-4 alkyl or C1-4 alkoxy, and the C1-4 alkyl and the C1-4 alkoxy are optionally substituted with one or more R?a; each Rja is independently D, F, Cl, Br or I;
  • X2 is . or S; or, X1 and X2 together with the atoms to which they are attached form a benzene ring;
  • RX4b1, RX4b2, RX4C1 and RX4C2 are independently H, D or C1-4 alkyl;
  • each Ra, Rc, Rd, Ra', Rb ⁇ Rc', Rd', Re and Rf are the same or different and are independently H, D, F, Cl, Br, I, CN, C1-4 alkyl or C1-4 alkoxy, wherein the C1-4 alkyl and the C1-4 alkoxy are optionally substituted by one or more Ria3; each Ry is independently D, F, Cl, Br or I; ring E is a 5-6 membered heterocycle, a partially saturated 5-6 membered heterocycle, a C3-6 carbocycle substituted by one or more R52, and a partially saturated C3-6 carbocycle substituted by one or more R52 ; the heteroatoms in the 5-6 membered heterocycle are selected from N and O, and the number of heteroatoms is 1 or 2; each R52 is independently N(R5a2R5b2), SH or OH; R ⁇ 2 and R ⁇ 2 are independently H or C1-4 alkyl; Ring F is
  • L2, L21 and L22 are independently a linking bond or a C1-4 alkylene group
  • m4 is 1;
  • certain groups in the isoindole-based compound represented by general formula (XI), its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof are defined as follows. The unmentioned groups are the same as those described in any embodiment of the present invention (collectively referred to herein as
  • X2 is NRX4b1, O or S; each group is as defined in any of the schemes of the general formula (XI) of the present invention.
  • the general formula (XI) is represented by the general formula V:
  • X2 is selected from . or s;
  • X3 is CR4aR4b; R4a and R4b are the same or different and are independently selected from H, D, F, Cl, Br, I, CN, C1-4 alkyl, or C1-4 alkoxy, wherein the C1-4 alkyl and C1-4 alkoxy are optionally substituted with one or more Rial; each Rial is independently D, F, Cl, Br, or I;
  • Gi, G2, G3 and G4 are the same or different and are independently selected from CH, CR2 or N;
  • R1 is independently D, F, Cl, Br, I, CN, Cl-4 alkyl or Cl-4 alkoxy, and the C1-4 alkyl and G-4 alkoxy are optionally substituted with one or more R1a2;
  • each R1a2 is independently D, F, Cl, Br or I;
  • X4 is selected from: or S;
  • Y1, Y2, Y3, Y4 and Y5 are the same or different and are independently selected from CH, CR3 or N; R3 is independently D, F, Cl,
  • R3C is independently D, F, Cl, Br, or I
  • R3a and R3b are the same or different and are independently selected from H, D, C1-4 alkyl, or C3-6 cycloalkyl
  • m is 0, 1, 2, or 3
  • carbon atoms marked with * are asymmetric centers
  • R° is selected from H, D or C1 alkyl
  • R? are the same or different and are independently selected from D, F, Cl, Br, I, CN, C1-4 alkyl, C1-4 alkoxy, wherein the C1-4 alkyl and the C1-4 alkoxy are optionally substituted by one or more R?a; each R?a is independently D, F, Cl, Br or I;
  • R, Rb, Rc, Rd, Re, and Rf are the same or different and are independently selected from H, D, F, Cl, Br, I, CN, C1-4 alkyl, or C1-4 alkoxy.
  • the C1-4 alkyl and C1-4 alkoxy groups are optionally substituted with one or more R1a3 ; each R1a3 is independently D, F, Cl, Br, or I; or, Ra and one of R1a3, and one of Rc and Rd and the carbon atom to which they are attached, together form a 3- to 6-membered ring, and the rest are independently selected from H, D, F, Cl, Br, I, CN, C1-4 alkyl, or C1-4 alkoxy.
  • the C1-4 alkyl and C1-4 alkoxy groups are optionally substituted with one or more R1a3; each R1a3 is independently D, F, Cl, Br, I, CN, C1-4 alkyl, and C1-4 alkoxy groups. When there are multiple substituents, the substituents are the same or different.
  • an isocyanate derivative represented by general formula (IA), and a pharmaceutically acceptable salt, solvate, crystal form, metabolite, prodrug or stereoisomer thereof: wherein X, X, X, X, X, G1, G2, G3, G4, Y1, Y2, Y3, Y4, Y5, R°, R1, R, R, R, R, *, and H1 are as defined in Formula (I).
  • an isocyanate derivative of Formula (IB), or a pharmaceutically acceptable salt, solvate, crystalline form, metabolite, prodrug, or stereoisomer thereof is also provided: Among them, X, X ⁇ X ⁇ X ⁇ G1, G2, G3, G4, Y1, Y2, Y3, Y4, Y5, R°, R1, R ⁇ R ⁇ R ⁇ R ⁇
  • an isocyanate derivative represented by Formula (LA-1), a pharmaceutically acceptable salt, solvate, crystalline form, metabolite, prodrug, or stereoisomer thereof is also provided: wherein X, X, X, X, X, G1, G2, G3, G4, Yi, Y2, Y3, Y4, Y5, R°, R, R, R, Rd , Re, Rf, and m are as defined in Formula (I).
  • an isocyanate derivative of Formula (LA-2), or a pharmaceutically acceptable salt, solvate, crystalline form, metabolite, prodrug, or stereoisomer thereof is also provided: Among them, X, X ⁇ X ⁇ X ⁇ G1, G2, G3, G4, Yi, Ya2, Ya3, Ya4, Ya5, R°, R, R ⁇ R ⁇ R ⁇ R d ,
  • an isocyanate derivative of Formula (LA-4), or a pharmaceutically acceptable salt, solvate, crystalline form, metabolite, prodrug, or stereoisomer thereof is also provided: Among them, X, X ⁇ X ⁇ X ⁇ G1, G2, G3, G4, Y1, Y2, Y3, Y4, Y5, R°, R1, R ⁇ R ⁇ R ⁇ R ⁇
  • Re, Rf, and m are as defined in general formula (I).
  • an isocyanate derivative represented by general formula (IB-1), a pharmaceutically acceptable salt, solvate, crystalline form, metabolite, prodrug, or stereoisomer thereof is also provided: Among them, X, X ⁇ X ⁇ X ⁇ G1, G2, G3, G4, Y1, Y2, Y3, Y4, Y5, R°, R1, R ⁇ R ⁇ R ⁇ R ⁇ R ⁇
  • Re, Rf, and m are as defined in general formula (I).
  • an isocyanate derivative represented by general formula (IB-2), or a pharmaceutically acceptable salt, solvate, crystalline form, metabolite, prodrug, or stereoisomer thereof is also provided: Among them, X, X ⁇ X ⁇ X ⁇ G1, G2, G3, G4, Y1, Y2, Y3, Y4, Y5, R°, R1, R ⁇ R ⁇ R ⁇ R ⁇ R ⁇
  • Re, Rf and m are as defined in the general formula (I).
  • an isocyanate derivative represented by general formula (IB-3), or a pharmaceutically acceptable salt, solvate, crystal form, metabolite, prodrug, or stereoisomer thereof is also provided:
  • X, X, X, X, G1, G2, G3, G4, Yi, Y2, Y3, Y4, Y5, R°, R, R, R, R, Rd , Re, Rf and m are as defined in Formula (I).
  • an isocyanate derivative represented by Formula (IB-4), a pharmaceutically acceptable salt thereof Among them, X, X ⁇ X ⁇ X ⁇ G1, G2, G3, G4, Yi, Ya2, Ya3, Ya4, Ya5, R°, R, R ⁇ R ⁇ R ⁇ R d ,
  • an isocyanate derivative represented by general formula (II), a pharmaceutically acceptable salt thereof, a solvent thereof is also provided.
  • X, X, G1, G2, G3, G4, Y1, Y2, Y3, Y4, Y5, R°, R, R, Rb , Rd, Rf , * and m are as defined in formula (I).
  • an isocyanate derivative represented by formula (III), a pharmaceutically acceptable salt thereof, a solvent thereof is also provided.
  • G1, G2, G3, G4, Y1, Y2, Y3, Y4, Y5, R ⁇ Rb, RC, Rd, Re, and * are as defined in general formula (I).
  • ml is 0 or 1;
  • m3 is 0, 1, 2, or 3;
  • R° is H or D
  • R1, R12, R13 and R14 are independently D or H;
  • ⁇ is independently D or F
  • X51 , X52, and X53 are 0;
  • X] is CD2, CHD or CH2;
  • X2 is 0; or, X1 and X2 together with the atoms to which they are connected form a benzene ring;
  • X 3 is CR 4a R 4b ; R4a and R4b are independently H or D; wherein Ring A is connected to X3; m2 is or 1; Ring A is independently a benzene ring;
  • Rx4bi is independently H, D or C1-4 alkyl; the C1-4 alkyl is optionally substituted with one or more D, F, Cl, Br or I;
  • RX4ai is L1-R5;
  • R5a is H,
  • R5b is H or C1-4 alkyl; the C1-4 alkylene group and C1-4 alkyl group are optionally substituted with one or more D , F, Cl, Br or I;
  • Zi is independently CH, CD or N;
  • Z2 is independently O, CH, CD or N; wherein, Z2 is connected to ring c, when Z2 is.
  • R, Rb, RC, Rd, Ra', Rb', RC', Rd', Re and Rf are independently H, D, F, Cl, C1-4 alkyl or C1-4 alkoxy, and ring E is a 5-6 membered heterocycle, a partially saturated 5-6 membered heterocycle, a C3-6 carbocycle substituted by one or more R52, or a C3-6 carbocycle substituted by one or more R52.
  • R52 substituted partially saturated C3-6 carbon ring; the heteroatom N in the 5-6 membered heterocyclic ring is 1; each R52 is independently is N(R5a2R5b2), SH or OH; R5a2 and R»2 are independently H or C1-4 alkyl; the ring E is optionally substituted with one or more D, F or C1; the ring C is a benzene ring or a 6-membered N-containing heteroaromatic ring;
  • R 3 is independently D, F, Cl, Br, I, CN, NO 2 , G-6 alkyl or G-6 alkoxy; wherein the G-6 alkyl and O- Cl, Br, or I; carbons marked with * are asymmetric centers.
  • ml is 0 or 1
  • m3 is 0, 1, 2, or 3;
  • R° is H or D
  • R1, R12, R13 and R14 are independently D or H;
  • ⁇ is independently D or F
  • X51 , X52, and X53 are 0;
  • X 3 is CR 4a R 4b ; R4a and R4b are independently H or D; wherein Ring A is connected to X3; m2 is . or 1; Ring A is a benzene ring;
  • X 14 is C(RX4alRX4bl);
  • Zi is independently CH, CD or N;
  • Z2 is independently CH, CD or N;
  • R, Rb, RC, Rd, Ra', Rb', Rc', Rd', Re and Rf are independently H, D, F, Cl, C1-4 alkyl or C1-4 alkoxy, and ring C is a benzene ring or a 6-membered N-containing heteroaromatic ring;
  • R3 is independently D, F, Cl, Br, CN, C-6 alkyl, or C-6 alkoxy; wherein the C-6 alkyl and C-6 alkoxy groups are optionally substituted with one or more R3C, each R3C being independently D, F, Cl, Br, or I; carbon atoms marked with * are asymmetric centers.
  • one of X51 and X52 is O and the other is S; for example, X51 is O and X52 is S, or X51 is S and X52 is O. In some embodiments, X51 and X52 are O. In some embodiments, X53 is independently O. In some embodiments, X53 is independently S. In some embodiments, each R1 is independently D, F, Cl, CN, CH3, CH2CH3, OCH3, OCH2CH3 , CD3, CH2F, CHF2, CF3 , OCD3, or OCF3; preferably, each Y is F.
  • each Y is independently D, F, Cl, CN, CH, CH2CH3, OCH3, OCH2CH3 , CD3, CH2F , CHF2, CF3, SF5, COOH, OCD3 , or OCF3.
  • each Y is independently F.
  • X is Se.
  • X is CD2, CHD, or CH2; for example, CH2.
  • X2 is O.
  • X2 is S.
  • X2 is Se.
  • X2 is NR, such as NH.
  • R4a and R4b are independently H, D, F, Cl, CN, CH3 , CD3, CHF2, CF3, SF5, CH2CH3, C2D5, OCH3, OCD3, OCHF2, OCF3 or OCH2CH3; preferably, R4a and R4b are independently H or D; more preferably, R4a and R4b are both H. In some embodiments, R4a and R4b are independently H, D, F, Cl, CN, CH3 , CD3, CHF2, CF3, CH2CH3,
  • X3 is CH2, CD2, CHF, CF2, CHCH3, CHCH2CH3, CHCD3, CHCF3, CHOCH3,
  • X3 is CH2 or CD2. More preferably, X3 >g CH 2.
  • X2 is. Or S, and X3 is CH2, CD2, CHF, CF 2 , CHCH3, C(CH 3 ) 2 or C HOCH3.
  • X2 is O, and X3 is CH2.
  • X2 is S, and X3 is CH2.
  • X2 is NR4bi, and X3 is CH2.
  • X is CH2, X2 is O, and X3 is CH2.
  • m2 is 0 or 1. In some embodiments, m2 is 0. In some embodiments, m2 is 1. In some embodiments, in the general formula (I), Gi, G2, G3 and G4 are the same or different and are independently selected from CH or
  • O, G2, G3, and G4 are CR2.
  • O, G2, and G3 are CH, and G4 is CH or CR2 .
  • O, G2, G3, and G4 are all CH.
  • O, G2, and G3 are CH, and G4 is CR2.
  • Rial is independently H.
  • R2M is independently H.
  • each R2 is independently D, F, Cl, CN, COOH, CH3 , CH2CH3, OCH3, OCH2CH3, CD3, CH2F, CHF2, CF3, SF5, OCD3 , or OCF3.
  • each R2 is independently D, F, Cl, CN, CH, CH2CH3, OCH3, OCH2CH3 , CD3 , CH2F, CHF2, CF3, OCD3, or OCF3; preferably, each R2 is F.
  • each R2 is independently D, F, Cl, CN, COOH, COOCH3, COOCH2CH3 , CH3, CH2CH3, OCH3, OCH2CH3, CD3, CH2F, CHF2, CF3, SF5, CH2CH2OH, CH2CH2NH2, OCH2CH2OH, OCH2CH2NH2, OCD3 , or OCF3.
  • the a-terminal is connected to X3
  • the b-terminal is connected to ring B.
  • RX4b, RX4b2, RX4C1 and RX4C2 are independently H, D, CH3 or 2H; for example, H, D or
  • L1 is independently a linker, -CH2-, or -C2H4-; for example, a linker or
  • R5a and R5b are independently H or CH3.
  • COOR5a is COOH.
  • R5 is NH2, NH(CH3), N(CH3)2, SH, or OH; for example, NH2, NH( CH3 ), or OH.
  • RX4al is NH2, NH(CH3), N(CH3)2, SH, OH, CH2NH2, CH2NH(CH3), CH2N(CH3)2, or CH2OH; for example, NH2, NH(CH3), OH, CH2NH2, CH2NH(CH3), or CH2OH.
  • L12 is independently a C1-6 alkylene group, such as -(CH2)-, -(CH2)2-, -( CH2 )2-, -(CH2) 2- , -( CH2 ) 2- , or -( CH2 ) 2- .
  • Rx is independently -NH-, -O-, -S-, or -Se-.
  • Ry is independently NH2, OH, SH, or SeH.
  • Ry is independently CH2OH. ,”, ⁇ /' ⁇ , ⁇ / ,,, X,, X,, or ),,.
  • N(RX4b1) is N(CH3).
  • C( ⁇ RX4c3) is C( ⁇ CH2).
  • R5M and R5U are H.
  • R5ai and R5bi are H, CH3, Boc, Cbz, Fmoc, C( ⁇ O) CH3 , or C( ⁇ O) CF3 .
  • R5i is NH2, SH, or OH.
  • R51 is NH2, SH, OH, NH(CH3), NH(Boc), NH(Cbz), NH(Fmoc), NHC( ⁇ O) CH3 , or NHC( ⁇ O) CF3 .
  • Ring D is a C3-6 carbocycle substituted with one or more R51, wherein the C3-6 carbocycle is, for example, cyclobutane.
  • Ring D is a 3-6 membered heterocyclic ring; for example, N-heterocyclobutane, . Heterocyclobutane; 0
  • Z1 is CH.
  • Zi is N.
  • Z2 is O.
  • Z2 is CH.
  • Z2 is N.
  • Zi is CH and Z2 is N.
  • Zi is N and Z2 is CH.
  • Zi is N and Z2 is N.
  • Z4 is O.
  • Z4 is NH.
  • Z4 is CH2.
  • X4 is selected from O.
  • X4 is selected from So In some embodiments, X4 is , or S, and Z1 is CH.
  • each of Ra, Rb, RC, Rd, Ra , Rb', Re, Rd, Re, and Rf is independently H, D, F,
  • each of Ra, Rb, RC, Rd, Ra', Rb ⁇ Rc', Rd] Re and Rf are independently H, D, F,
  • each Ra, Rb, Rc, Rd, Re and Rf are independently H, D, F or CH3. In some embodiments, each Ra, Rb, Rc, Rd, Ra', Rb ⁇ Rc', Rd', Re and Rf are H. In some embodiments, Ra and one of Rb and one of Rc and Rd together with the carbon atom to which they are attached form a 3-membered ring or
  • 4-membered ring the remaining U are independently H, D, F, Cl, Br, CN, CH3, CF3, SF5, C2H5, OCH3, OCF3 or OC2H5; the 3-membered ring or 4-membered ring is optionally substituted with one or more substituents selected from D, halogen, CN, C-4 alkyl and C-4 alkoxy. When there are multiple substituents, the substituents are the same or different.
  • the 3-membered ring or 4-membered ring is optionally substituted with one or more substituents selected from D, halogen, CN, C1-4 alkyl, and C1-4 alkoxy . When there are multiple substituents, the substituents may be the same or different. In some embodiments, R and one of Rb, and R and one of Rd, together with the carbon atom to which they are attached, form a 3-membered ring, and the remaining substituents are independently selected from H.
  • the 3-membered ring is optionally substituted with one or more substituents selected from D, F, Cl, Br, CN, CH3, C2H5, OCH3, or OC2H5. When there are multiple substituents, the substituents may be the same or different.
  • Y3 is CR3, any one of Y1, Y2, Y4, and Y5 is CR3, and the others are CH. In some embodiments, in the general formula (I), Y3 is CR3, any one of Y1 and Y5 is CR3, and the others are CH. In some embodiments, in the general formula (I), Y3 is CR3, any one of Y2 and Y4 is CR3, and the others are CHO. In some embodiments, in the general formula (I), Y1, Y2, Y3, Y4 and Y5 are the same or different and are independently selected from
  • Ring F is a pyrrole ring or a 1,3-diazoquinoline ring.
  • each R 3 is independently F, Cl, Br, CN, CH 3 -alkyl, CH 3 -alkoxy, cycloalkyl or
  • each R3C is independently D, F, or Cl.
  • R3a and R3b are the same or different and are each independently H, D, or C1-3 alkyl. In some embodiments, each is independently COOH.
  • each R3 is independently D, F, Cl, Br, CN, NCh, CH3, CF3, SF5, CD3, C2H5, In some embodiments, each R3 is independently D, F, CN, OCH3, OCF3, OCD3 , bovine or human N. In some embodiments, each R3 is independently D, F, CN, CH, OCH3, OCF3 or OCD3; for example, D, F, CN,
  • L2, L21 and L22 are connecting bonds.
  • L2, L21, and L22 are independently Cl-4 alkylene; preferably, methylene (-CH2-), ethylene ⁇ e.g., -CH2CH2- or -CH(CH3)- ⁇ , isopropylidene ⁇ e.g., -CH( CH3 ) CH2- , -CH2CH ( CH3 )-, or -C(CH3)2- ⁇ , or n - butylidene (-( CH2 )4-); e.g., -(CH2)2-.
  • RL3a is H or methyl.
  • RL3b is independently D, F, Cl, Br, I, or methyl; e.g., methyl.
  • each Ci' alkylene group is independently methylene (-CH2-), ethylene ⁇ e.g.
  • each C3-6 cycloalkylene is independently cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene.
  • each C3-6 cycloalkylene group is independently / , 'd, , ⁇ , / ', d
  • L3 and L31 are independently C1-4 alkylene, preferably -(CH2)-, -(CH2)2-, -C(CH3)2-, -C(CH3)2-CH2-, or -(CH2)4-.
  • L3 and L31 are independently C1-4 alkylene-O-, preferably -( CH2 )-O-, -( CH2 )2-O-, -C( CH3 ) 2-
  • L3 and L31 are independently C1-4 alkylene-S-, preferably
  • L3 and L31 are independently C1-4 alkylene-Se-, preferably, -(CH2)-Se-, -( CH2 ) 2- Se-, -C( CH3 ) 2- Se- or -C(CH3)2-CH2-Se-; for example, -( CH2 ) 2 -Se-.
  • L3 and L31 are independently C1-4 alkylene-N(RL3a)-, preferably -Clfc-NH-, -(CH2)2-NH-, -C( CH3 )2-NH- or -C(CH3)2-CH2-NH-.
  • L3 and L31 are independently C3-6 cycloalkylene optionally substituted with one or more RL3b; the C3-6 cycloalkylene is preferably cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene.
  • L3 and L31 are independently ''O or -''O, and the yd end indicates connection with L2 or L21; for example, L3 and L31 are independently One or more are independently D, F or methyl; for example, methyl;
  • the C3-6 cycloalkylene group is 2d, Xd or Xdd end connected to a C1-4 alkylene group; for example, the C1-4 alkylene group is -CH2-, -CH2CH2-; for example -CH2 -O
  • L3 and L31 are independently C3.6 cycloalkylene-Cl-4 alkylene-S-; Preferably independently D, F or methyl; eg methyl;
  • L3 and L31 are independently C3-6 cycloalkylene-C1-4 alkylene-Se-; wherein the C3-6 cycloalkylene is preferably a cyclopropylene or cyclobutylene optionally substituted with one or more RL3b; each
  • R6C1 is NH2, NH(CH3), SH, OH or CH3.
  • the 3-6 membered heterocycloalkyl is N-heterobutyl, oxetanyl, piperazinyl or
  • R4 is , and R5 is , , , , , . In some embodiments, R4 is , and R5 is , , , , . In some embodiments, or a combination thereof.
  • the b end indicates that it is connected to ring B.
  • (R2)m2b In some embodiments, dr ⁇ , a is '" or COOH; the a end represents connection with X', and the b end represents connection with ring B.
  • the anisotropic compound represented by general formula (XI) is any of the following structures:
  • the pharmaceutically acceptable salt of the isopropyl alcohol compound represented by general formula (XI) is any of the following structures:
  • CM-162-P2 The mobile phase was ethanol (containing 0.1% diethylamine)/CO2
  • CM-163-P1 mobile phase is ethanol (containing 0.1% diethylamine)/CO2
  • the pharmaceutically acceptable salt of the isocyanate compound represented by general formula (XI) is any of the following structures:
  • Another aspect of the present invention relates to a method for preparing an isoindole compound represented by general formula (X), the method comprising the following schemes: Scheme 1, comprising the following steps: The compound represented by the general formula (XI) undergoes an intramolecular ring-closing reaction to obtain an iso-hum noise ⁇ forest compound represented by the general formula (X); wherein Rm is Cl-6 alkyl; preferably tert-butyl;
  • X, X ⁇ X ⁇ R°, Ri, R3, R4, ml, m3, m4, *, L and ring C are as defined in general formula (X); further, the method may further include: The compound represented by the general formula (X2) reacts with the compound represented by the general formula (X3) to obtain an isocyanate compound represented by the general formula (XI); wherein Rm is a C1-6 alkyl group; preferably a tert-butyl group; wherein M is a leaving group; preferably Cl, Br or OMs; more preferably Cl or Br;
  • Ri, R3, R 4 , ml, m3, m4, *, L and ring C are as defined in the general formula (X);
  • the compound represented by the general formula (X4) reacts with the compound represented by the general formula (X3) to obtain an isocyanate compound represented by the general formula (X); wherein M is a leaving group; preferably Cl, Br or OMs; more preferably Cl or Br;
  • Scheme 3 comprises the following steps: when the compound represented by general formula (X) is general formula (Xe), the compound represented by general formula (X6) undergoes a deprotection group Q reaction to obtain a compound represented by general formula (Xe);
  • R6-1 is N(R6a), . or S; preferably N(R6a);
  • Q is N, . or S protecting group;
  • N protecting group is preferably Boc;
  • the present invention relates to a method for preparing a compound represented by formula (I), a stereoisomer, or a pharmaceutically acceptable salt thereof, comprising: The compound represented by general formula (Ia) undergoes an intramolecular ring-closing reaction to obtain a compound represented by general formula (I); wherein Rm is a C1-6 alkyl group; preferably a tert-butyl group;
  • the method further comprises: The compound represented by general formula (Ib) reacts with the compound represented by general formula (Ic) to obtain the compound represented by general formula (Ia); wherein Rm is a C1-6 alkyl group; preferably a tert-butyl group; wherein M is a leaving group; preferably C1 or Br;
  • the present invention relates to a method for preparing a compound, stereoisomer, or pharmaceutically acceptable salt thereof represented by Formula (I), comprising: The compound represented by general formula (Id) reacts with the compound represented by general formula (Ic) to obtain the compound represented by general formula (I); wherein M is a leaving group; preferably Cl or Br;
  • the present invention relates to a method for preparing a compound represented by Formula (LA), a stereoisomer, or a pharmaceutically acceptable salt thereof, comprising:
  • the compound represented by the general formula (IAa) undergoes an intramolecular ring-closing reaction to obtain a compound represented by the general formula (IA); wherein Rm is a Cl-6 alkyl group; preferably a tert-butyl group;
  • the present invention relates to a method for preparing a compound represented by Formula (LB), a stereoisomer, or a pharmaceutically acceptable salt thereof, comprising:
  • the compound represented by the general formula (IBa) undergoes an intramolecular ring-closing reaction to obtain a compound represented by the general formula (LB); wherein Rm is a C1-6 alkyl group; preferably a tert-butyl group;
  • the present invention relates to a method for preparing a compound represented by Formula (IA-1), Formula (IA-2), Formula (IA-3), Formula (IA-4), Formula (IB-1), Formula (IB-2), Formula (IB-3), and/or Formula (IB-4), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the method comprising: subjecting the compound represented by Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to chiral resolution; Obtaining compounds represented by General Formula (IA-1), General Formula (IA-2), General Formula (IA-3), General Formula (IA-4), General Formula (IB-1), General Formula (IB-2), General Formula (LB-3) and/or General Formula (IB-4), stereoisomers, or pharmaceutically acceptable salts thereof;
  • Another aspect of the present invention relates to an isocyanate compound represented by formula (XI), (X3), or (X6), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof (an intermediate for preparing an isocyanate compound represented by formula (XI) above): Wherein, Rm is H or G-6 alkyl; preferably tert-butyl;
  • M is a leaving group; preferably Cl, Br or OMs; more preferably Cl or Br;
  • RE is N(R6a), . or S; preferably N(R6a);
  • Q is a N, . or S protecting group; the N protecting group is preferably Boc;
  • the present invention relates to an isocyanate derivative, stereoisomer, or pharmaceutically acceptable salt thereof represented by general formula (Ia): Wherein, Rm is a C1-6 alkyl group; preferably a tert-butyl group;
  • M (D or 2H) is a stable, non-radioactive isotope of hydrogen with an atomic weight of 2.0144.
  • Natural hydrogen exists as a mixture of H (hydrogen or thiophene), D (H or 2H), and T (3H or 2H) isotopes, with the abundance of 2H being 0.0156%.
  • the hydrogen atoms actually represent a mixture of H, D, and T. Therefore, compounds with a 2H abundance greater than 0.0156% of its natural abundance at any site in the compound should be considered unnatural or 2H-enriched, and therefore novel relative to their non-enriched counterparts.
  • “D”, “deoxyribonucleic acid” or “deoxyribonucleic acid-enriched” compound means that the abundance of deoxyribonucleic acid at any relevant site in the aforementioned isocyanate compound, its pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, metabolite or prodrug compound is greater than its natural abundance at the site. Therefore, in the "D”, “deoxyribonucleic acid” or “deoxyribonucleic acid-enriched” compound, the abundance of deoxyribonucleic acid at any of its relevant sites may be in the range of greater than 0.0156% to 100%.
  • Deoxyribonucleic acid-enriched sites are represented by D, and non-deoxyribonucleic acid-enriched sites are represented by H. According to common technical knowledge in the art, the symbol H can also be omitted for non-deoxyribonucleic acid-enriched sites.
  • Examples of methods for obtaining deoxyribonucleic acid-enriched compounds are exchanging hydrogen with deoxyribonucleic acid or synthesizing compounds using deoxyribonucleic acid-enriched starting materials.
  • the percentage of ladle in the ladle enrichment or the percentage of ladle in the ladle abundance are all molar percentages.
  • non-ladle enrichment refers to hydrogen in nature, that is, in the form of H (hydrogen or H, DfH or ladle) and H (H or ladle) isotopic mixtures.
  • the compounds of the present invention include other isotopic compounds.
  • isotopic compound refers to a compound whose structure differs only in the presence of one or more Compounds with isotopically enriched atoms.
  • compounds having the structure of the present invention in which hydrogen is replaced by "N” or “N” or fluorine is replaced by 18F-fluorine label (18F isotope), or carbon atoms are replaced by nC- , 13C- , or 18C-enriched carbon (e.g., 18C-, 18C-, or 18C-carbon label; 18F-, 18C-, or 18C-isotope) are all within the scope of the present invention.
  • Such compounds can be used, for example, as analytical tools or probes in biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamic, pharmacokinetics, or receptor studies.
  • substituted forms are compounds in which each available hydrogen atom attached to a carbon atom can be independently replaced by an ion atom.
  • substituted starting materials can be used to prepare substituted compounds, or they can be synthesized using substituted reagents using conventional techniques.
  • substituted agents include, but are not limited to, substituted borane, trisubstituted borane tetrahydrofuran solution, substituted lithium aluminum hydride, substituted iodoethane and substituted iodomethane, etc.
  • Substituted substances can generally retain activity comparable to unsubstituted compounds, and when substituted at certain specific sites, better metabolic stability can be achieved, thereby obtaining certain therapeutic advantages. in,
  • L is a linker, which covalently binds Tb and D;
  • D is a biologically active compound fragment, wherein D is an isocyanate compound represented by formula (XI) as described in any of the preceding schemes, its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof.
  • the present invention also provides a pharmaceutical composition comprising (a therapeutically and/or prophylactically effective amount of) the aforementioned isocyanate compound, its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof, or the aforementioned antibody-drug conjugate, and pharmaceutically acceptable excipients.
  • the pharmaceutical composition can be formulated for any form of administration, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical, or parenteral (infusion, injection, implant, subcutaneous, intravenous, intraarterial, intramuscular) administration.
  • the pharmaceutical composition of the present invention can also be in a controlled-release or delayed-release dosage form.
  • solid oral dosage forms include, but are not limited to, powders, capsules, caplets, softgels, and tablets.
  • liquid formulations for oral or transmucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions.
  • topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serums.
  • formulations for parenteral administration include, but are not limited to, injectable solutions, dry preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, injectable suspensions, and injectable emulsions.
  • Examples of other suitable formulations of the aforementioned isocyanate compounds, their pharmaceutically acceptable salts, solvates, crystalline forms, metabolites, prodrugs, or stereoisomers include, but are not limited to, eye drops and other ophthalmic preparations; aerosols such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories; and lozenges.
  • Pharmaceutically acceptable excipients in the pharmaceutical compositions according to the present invention include those widely used in pharmaceutical production. Excipients are primarily used to provide a safe, stable, and functional pharmaceutical composition. They can also provide methods to ensure that the active ingredient dissolves at a desired rate after administration to a subject, or to promote effective absorption of the active ingredient after administration of the composition to a subject.
  • Pharmaceutically acceptable carriers can take a variety of forms depending on the desired dosage form for administration.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, colorants, and the like.
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrants, and the like.
  • Pharmaceutically acceptable excipients should generally be non-toxic.
  • Pharmaceutical compositions according to the present invention may include one or more suitable excipients. The amount and type of excipient will vary as needed.
  • compositions of the present invention comprising (a therapeutically or prophylactically effective amount of) the aforementioned isocyanate compounds, stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or the aforementioned antibody-drug conjugates, can be prepared using any method known to those skilled in the art based on the disclosed disclosure.
  • the pharmaceutical compositions of the present invention can be prepared by mixing the aforementioned isocyanate compounds, stereoisomers, tautomers, or pharmaceutically acceptable salts thereof with a pharmaceutically acceptable carrier using conventional pharmaceutical formulation techniques, including but not limited to conventional mixing, dissolution, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.
  • the pharmaceutical compositions may further comprise one or more other therapeutic agents in addition to one or more of the aforementioned isocyanate compounds, stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or the aforementioned antibody-drug conjugates. Further details on the other therapeutic agents that may be included in the pharmaceutical compositions of the present invention are disclosed below.
  • a therapeutic or preventive amount of the aforementioned isocyanate compounds, stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or the aforementioned antibody-drug conjugates, or any pharmaceutical compositions or formulations thereof can be administered to a subject in accordance with the methods of the present invention over a period of time (a dosing cycle), followed by a period in which the compound is not administered (a non-dosing cycle).
  • the dosing and non-dosing cycles can be repeated as many times as desired.
  • the desired length and number of dosing or non-dosing cycles will depend on the type and/or severity of the disease, disorder, or condition being treated or prevented, as well as the sex, age, weight, and other parameters of the subject (e.g., the biological, physical, and physiological condition of the subject). Based on the disclosure herein, a person of ordinary skill in the art will be able to determine the appropriate length and number of dosing cycles and/or non-dosing cycles.
  • the isocyanate compounds, stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or the aforementioned antibody-drug conjugates, of the present invention when used in combination with other therapeutic agents, can exert a synergistic effect in the treatment or prevention of any disease, disorder, or condition.
  • a composition comprising an isocyanate compound, stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or the aforementioned antibody-drug conjugates, and another therapeutic agent is administered simultaneously to a subject.
  • the isocyanate compounds, stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and the other therapeutic agent are administered sequentially.
  • the aforementioned isocyanate compound, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt, or the aforementioned antibody-drug conjugate, and another therapeutic agent are administered separately; the other therapeutic agent is administered separately.
  • the therapeutic agent can be administered before, concurrently with, or after administration of the isocyanate compounds, stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or the antibody-drug conjugates described above.
  • the one or more other therapeutic agents that may be administered in combination with the isocyanate compounds, stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or the antibody-drug conjugates described above will depend on various factors, such as the disease, disorder, or condition to be prevented or treated.
  • the other therapeutic agent may be a naturally occurring, semisynthetic, or synthetic compound.
  • the other therapeutic agent may be a small molecule, such as a synthetic organic or inorganic molecule, or a larger molecule or biomolecule, such as a pharmacologically active protein or nucleic acid.
  • the other therapeutic agent can be an anti-angiogenic, immunomodulatory, immunotherapeutic, chemotherapeutic, or hormonal compound.
  • the therapeutically effective amount of the aforementioned isocyanate compound, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt, or the aforementioned antibody-drug conjugate is lower than the therapeutically effective amount required when the aforementioned isocyanate compound, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt, or the aforementioned antibody-drug conjugate is not administered in combination with the other therapeutic agent.
  • the therapeutically effective amount of the other therapeutic agent is lower than the therapeutically effective amount when the aforementioned isocyanate compound, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt, or the aforementioned antibody-drug conjugate is not administered.
  • the aforementioned isocyanate compounds, stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or the aforementioned antibody-drug conjugates, and other therapeutic agents when administered to a subject to treat or prevent a disease, disorder, or condition, the aforementioned isocyanate compounds, stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or the aforementioned antibody-drug conjugates, and other therapeutic agents may be administered via the same route or different routes.
  • the other therapeutic agent may be administered via any route described herein, including but not limited to oral, inhalation, injection, ocular, mucosal, rectal, emulsion, liposome, long-acting implant, or sustained-release methods.
  • the specific route of administration of the other therapeutic agent will depend on the other therapeutic agent itself and its formulation, as well as the disease, disorder, or condition to be prevented or treated.
  • the aforementioned isocyanate compounds, their stereoisomers, their tautomers, or their pharmaceutically acceptable salts, or the aforementioned antibody-drug conjugates, or the aforementioned pharmaceutical compositions of the present invention can have a variety of uses, including but not limited to use in the preparation of medicaments for treating or preventing diseases, disorders, or conditions (CRBN protein-related diseases); or use in the preparation of medicaments for treating or treating cancer; or use in the preparation of medicaments for treating or treating multiple myeloma.
  • the present invention relates to a method for treating a disease, disorder, or condition by administering to a subject the aforementioned isocyanate compounds, their stereoisomers, their tautomers, or their pharmaceutically acceptable salts, or the aforementioned antibody-drug conjugates, or the aforementioned pharmaceutical compositions.
  • the disease, disorder, or condition is a CRBN protein-related disease.
  • the disease, disorder, or condition is preferably a disease, disorder, or condition associated with inducing ubiquitination and degradation of a target protein in cells.
  • the disease, disorder, or condition is preferably cancer, such as a hematological cancer or a solid cancer.
  • the disease, disorder, or condition is preferably multiple myeloma.
  • stereoisomers refers to all stereoisomers, including enantiomers, diastereomers, epimers, endo-exo isomers, atropisomers, regioisomers, cis- and trans-isomers.
  • stereoisomers herein also include "pure stereoisomers,””enrichedstereoisomers,” or “racemates” of the aforementioned stereoisomers, as well as mixtures thereof.
  • stereoisomers can be separated, purified, and enriched through asymmetric synthesis or chiral separation methods (including but not limited to thin-layer chromatography, rotary chromatography, column chromatography, gas chromatography, high-pressure liquid chromatography, etc.). They can also be obtained by chiral resolution through bonding (chemical bonding, etc.) or salt formation (physical bonding, etc.) with other chiral compounds.
  • “Pure stereoisomers” herein refer to compounds in which the mass content of one stereoisomer relative to the mass content of the other stereoisomers of the compound is no less than 95%.
  • Enriched stereoisomers herein refer to compounds in which the mass content of one stereoisomer relative to the mass content of the other stereoisomers of the compound is no less than 50%.
  • Racemates herein refer to compounds in which the mass content of one stereoisomer is equal to the mass content of the other stereoisomers of the compound.
  • groups and substituents can be selected by those skilled in the art to provide stable moieties and compounds. When substituents are described using conventional chemical formulas written from left to right, such substituents also include chemically equivalent substituents when the formula is written from right to left.
  • C1-C4 alkyl or C1-C4 alkyl refers to an alkyl group, as defined below, having a total of 1, 2, 3, or 4 carbon atoms.
  • the total number of carbon atoms in the simplified notation does not include carbon atoms that may be present in substituents of the group.
  • the term “comprising” is open-ended, meaning that it includes the content specified in the present invention but does not exclude other aspects.
  • the terms "moiety,”"structuralmoiety,””chemicalmoiety,””group,” and “chemical group” refer to specific fragments or functional groups in a molecule.
  • a chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.
  • substituents of the compounds disclosed herein are disclosed in terms of group types or ranges. Specifically, the present invention includes each independent subcombination of the individual members of these group types and ranges.
  • the term "Cx-Cy alkyl” or “Cx-y alkyl” refers to a straight-chain or branched saturated hydrocarbon containing x to y carbon atoms.
  • Cx-Cy alkyl or “Cx-y alkyl” specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups
  • C1-4 alkyl specifically refers to the independently disclosed methyl, ethyl, C3 alkyl (i.e., propyl, including n-propyl and isopropyl), and C4 alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl).
  • the numerical ranges defined in the substituents such as 0 to 10, 1-6, 1-3, etc., indicate integers within the range, such as 1-6 means 1,
  • substituents When a substituent is listed without specifying the atom through which it is bonded to the general chemical formula (including compounds not specifically mentioned), such substituent may be bonded via any atom thereof. Combinations of substituents and/or their variants are permissible only if such combinations result in stable compounds.
  • substituted or “substituted by” refers to the replacement of any one or more hydrogen atoms on a specified atom with a substituent, provided that the valence of the specified atom is normal and the resulting compound is stable. Generally, the term “substituted” or “substituted” means that one or more hydrogen atoms in a given structure are replaced with a specified substituent.
  • the substituents are independent of each other; that is, the one or more substituents may be different or the same.
  • a substituent may be substituted at every substitutable position of the substituted group.
  • the substituents may be the same or different at each position.
  • any variable e.g., R"a
  • the definition of that variable at each occurrence is independent of the definitions at the remaining occurrences; their meanings are independent of each other and do not affect each other.
  • R"a a group is substituted with one, two, or three R"a groups, that is, the group may be substituted with up to three R"a groups
  • the definition of R"a at any one position is independent of the definitions at the remaining positions.
  • combinations of substituents and/or variables are permitted only if they result in stable compounds.
  • the term "optionally substituted with one or more R"a” refers to both unsubstituted R"a and substituted with one or more R "a.
  • the C1-6 alkyl in the -Z1-6 -C1-6 alkyl group is optionally substituted with one or more R"a” refers to both -Z1-6 -C1-6 alkyl and -Z, C1-6 alkyl (substituted with one or more R"a).
  • R the group is listed without explicitly stating that it has substituents, the group is considered unsubstituted.
  • alkyl refers to a saturated aliphatic hydrocarbon group, including branched and straight chains, having a specified number of carbon atoms, consisting solely of carbon atoms and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6, and most preferably 1 to 4) carbon atoms, and connected to the rest of the molecule by a single bond, wherein propyl is a C3 alkyl group (including isomers, such as n-propyl or isopropyl); butyl is a C4 alkyl group (including isomers, such as n-butyl, sec-butyl, isobutyl, or tert-butyl); and pentyl is a C5 alkyl group (including isomers, such as n-pentyl, 1-methyl-butyl
  • Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, nonyl, and decyl, and similar alkyl groups.
  • Preferred are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl.
  • Linking substituents are described in various sections of the present invention.
  • the Markush variable listed for that group should be understood to be a linking group.
  • the alkyl represents a linking alkylene group.
  • the alkyl group represents a linking alkylene group.
  • the C1-6 alkyl in the group "halo-C1-6alkyl” should be understood to refer to C1-6alkylene.
  • alkylene refers to a saturated divalent hydrocarbon group derived by removing two hydrogen atoms from a saturated straight or branched hydrocarbon; that is, one hydrogen in an alkyl group is replaced, and the definition of alkyl is as described above.
  • alkylene groups include methylene (-CH2-), ethylene ⁇ including -CH2CH2- or -CH( CH3 )- ⁇ , isopropylidene ⁇ including -CH( CH3 ) CH2- , -CH2CH ( CH3 )- or -C(CH3)2- ⁇ , and n-butylidene (-(CH2)4-), among others.
  • alkoxy refers to -O-(alkyl), where alkyl is as defined above.
  • alkoxy groups include methoxy, ethoxy, propoxy, and butoxy.
  • alkylamino refers to an amino group substituted by one or two identical or different alkyl groups, and can be represented by -NH-(alkyl) or -N-(alkyl)2, wherein the alkyl group is as defined above; when there are two alkyl groups, the two alkyl groups can be the same or different.
  • Non-limiting examples of alkylamino groups include: -NH-CH3, -NH-C2H5, -N( CH3 )2, -N( C2H5 ) 2 , and -N( CH3 ) -C2H5O .
  • cycloalkyl refers to a saturated monocyclic or polycyclic hydrocarbon substituent.
  • the cycloalkyl group includes 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups.
  • the term "carbocycle” refers to a saturated monocyclic or polycyclic hydrocarbon. The carbocycle comprises 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms.
  • Non-limiting examples of saturated monocyclic carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclopentane, cyclohexane, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkanes.
  • heterocyclo(alkyl) refers to a stable, saturated, monocyclic or polycyclic (e.g., bicyclic, tricyclic, or more cyclic, bridged, fused, or spirocyclic) non-aromatic cyclic group composed of carbon atoms and 1, 2, 3, 4, 5, or 6 heteroatoms selected from N, S, and S; preferably, a 3-6 membered heterocyclic group comprising 1 or 2 heteroatoms selected from N and S.
  • Exemplary 3-membered heterocycloalkyl groups include, but are not limited to, aziridine, oxiranyl, and thiirane, or stereoisomers thereof;
  • exemplary 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl (for example), oxiranyl, oxetane (for example, 7), thiirane, or isomers and stereoisomers thereof;
  • exemplary 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophene, pyrrolidinyl (for example, 15), 15-17.
  • the group includes, but is not limited to, piperyl, tetrahydropyranyl, cyclopentylsulfide, morpholinyl, thiomorpholinyl, dithioalkyl, dioxane alkyl, piperazinyl, triazinyl, or isomers and stereoisomers thereof.
  • heterocycle refers to a stable, saturated, monocyclic or polycyclic (e.g., bicyclic, tricyclic, or more cyclic, bridged, fused, or spirocyclic) non-aromatic ring composed of carbon atoms and 1, 2, 3, 4, 5, or 6 heteroatoms selected from N, Cr, and S; preferably, a 3- to 6-membered heterocycle containing 1 or 2 heteroatoms selected from N and Cr.
  • Exemplary 4-membered heterocycloalkyl groups include, but are not limited to, azetidine, oxetane, or isomers and stereoisomers thereof.
  • aryl refers to an aromatic group consisting of a conjugated cyclic ring system of carbon atoms that satisfies the 4n+2 rule, with each ring being aromatic.
  • aryl refers to an aromatic group having 6 to 18 (preferably 6 to 10) carbon atoms. Examples of aryl include, but are not limited to, phenyl or naphthyl.
  • heteroaryl refers to a ring system group having carbon atoms and 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the heteroaryl group contains 5-6 members and 1 or 2 heteroatoms selected from N, more preferably, a 5-membered heteroaryl group containing 1 or 2 heteroatoms selected from N.
  • heteroaryl groups include, but are not limited to, thienyl, imidazole, pyrazolyl, thiazolin ... blood), chloranil, chloranil, isochloranil, pyrimethamine Pyridazinyl, furanyl, pyrrole
  • heteroaromatic ring means a ring system having carbon atoms and 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heteroaromatic ring comprises 5-6 members and 1 or 2 heteroatoms selected from N, more preferably, the heteroaromatic ring comprises 5 members and 1 or 2 heteroatoms selected from N.
  • heteroaromatic rings include, but are not limited to, thiophene, imidazole, pyridine (e.g.,
  • N ⁇ N H"X pyrazine, pyridazine, pyran, pyrrole, triazole (such as triazole or triazole), tetraazole, triazine, oxazine.
  • triazole such as triazole or triazole
  • tetraazole triazine, oxazine.
  • heteroaryl groups include but are not limited to
  • JS is limited to VN, ...
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • “optionally” or “optionally” means that the subsequently described event or circumstance may but need not occur, and its meaning includes situations where the event or circumstance occurs or does not occur.
  • C3-6 cycloalkyl is optionally substituted with halogen means that halogen may but need not be present, and this description includes situations where the C3-6 cycloalkyl is substituted with halogen and situations where the C3-6 cycloalkyl is not substituted with halogen.
  • R n
  • the term “subject” refers to any animal, preferably a mammal, and most preferably a human, that is about to be or has been administered a compound or composition according to an embodiment of the present invention.
  • the term “mammal” includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.
  • treating refers to the improvement, prevention, or reversal of a disease or condition or at least one discernible symptom thereof, such as the treatment of cancer or an undesirable angiogenesis-related condition by reducing or stabilizing symptoms of the cancer or condition.
  • “treating” or “treating” refers to the improvement, prevention, or reversal of at least one measurable physical parameter of the disease or condition being treated, and the disease or condition may not be identified in the mammal.
  • “treating” or “treating” refers to slowing the progression of a disease or condition, either physically, such as stabilization of discernible symptoms, or physiologically, such as stabilization of a bodily parameter, or both.
  • treating refers to delaying the onset of a disease or condition.
  • the compounds of interest are administered as a prophylactic measure.
  • preventing refers to reducing the risk of acquiring a given disease or condition.
  • a given compound is administered to a subject, such as a subject with a family history or predisposition to cancer or an autoimmune disease, as a prophylactic measure.
  • a "therapeutically effective amount” refers to an amount of a compound or composition that is capable of eliciting the biological or medical response being sought by a researcher, veterinarian, medical doctor, or other clinician in a tissue system, animal, or human, which may include alleviating the symptoms of the disease or condition being treated.
  • a therapeutically effective amount is effective to treat, ameliorate, or prevent cancer, a disorder, or an undesirable vascular condition.
  • prophylactically effective amount refers to an amount of an active compound or agent that is capable of inhibiting the onset of a disorder being treated by a researcher, veterinarian, medical doctor, or other clinician.
  • a prophylactically effective amount of a compound is an amount of a therapeutic agent, alone or in combination with other therapeutically active compounds, that provides a therapeutic benefit in treating or preventing a disease, disorder, or condition.
  • the singular forms "a” or “an” include the plural unless otherwise specified.
  • “or” or “and” means “and/or” unless otherwise specified. Unless otherwise specified, "" or “” appearing in specific groups herein refers to the position of attachment. The above preferred conditions can be arbitrarily combined, without violating common knowledge in the art, to obtain preferred embodiments of the present invention.
  • the reagents and raw materials used in the present invention are commercially available.
  • the positive effects of the present invention are that the isocyanate compounds of the present invention can induce ubiquitination and degradation of target proteins in cells, thereby effectively treating cancer and other related diseases.
  • Experimental data demonstrate that the compounds of the present invention have a strong inhibitory effect on multiple myeloma and exhibit good stability.
  • DETAILED DESCRIPTION OF THE INVENTION The present invention is further illustrated by way of examples below, but the invention is not limited to the scope of the examples described. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or according to the product specifications. Example 1.
  • TBDMSCK tert-butyldimethylsilyl chloride, 33.2 g, 220 mmol
  • the reaction mixture was concentrated under reduced pressure, and ethyl acetate (250 mL) and water (250 mL) were added.
  • the organic phase was separated.
  • the aqueous phase was stripped with ethyl acetate (250 mL).
  • the combined organic phases were washed sequentially with water (250 mL) and saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 3, which was used directly in the next reaction.
  • Step 4 Compound 4 (5.00 g, 13.9 mmol) and compound 5 (CAS 108607-02-9, 3.65 g, 15.3 mmol) were dissolved in anhydrous acetonitrile (50 mL). Diisopropylethylamine (5.20 mL, 40 mL) was added dropwise at room temperature (30°C) under a nitrogen atmosphere. 29.2 mmol/l, heat to 40°C, and stir overnight. The reaction mixture was concentrated under reduced pressure, diluted with dichloromethane (100 mL), washed with water (50 mL x 2), saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a light yellow oil.
  • Step 2 To a solution of compound 7 (50 g, 214.35 mmol) in THF (500 mL) was added diethylzinc (1 M, 1.07 L, 1.29 mol) under ice-cooling, maintaining the internal temperature at 10-15°C. Then, a solution of CH 2 I 2 (574.11 g, 2.14 mol) in THF (500 mL) was added dropwise at 0-10°C. The resulting mixture was stirred in an ice-bath at 5-10°C for 1 hour. The mixture was then stirred at 30°C for 16 hours under N4 protection. 1N HCO (1 L) was added dropwise in an ice bath, and the mixture was extracted with ethyl acetate (1 L x 3).
  • IM-2 can be subjected to chiral resolution to obtain a single stereoisomer.
  • IM-2 is used as an intermediate in subsequent synthetic reactions.
  • derivatives of IM-2 with different substituents and their stereoisomers can be prepared by replacing the starting materials and/or reagents and adjusting the reaction conditions as usual. Some of these are listed below:
  • Example 3. Synthesis of IM-3 Step 1. Compound 1 M-3A (10.00 g, 0.0719 mol), 1-Boc-piperazine (13.39 g, 0.0719 mol) and potassium carbonate (49.69 g, 0.3595 mol) were added to RM dimethylacetamide (100 mL). (2) Stirred under nitrogen for 16 hours.
  • lithium borohydride (3.22 g, 0.148 mol) was slowly added to a solution of compound IM-4C (8.0 g, 0.0185 mol) in tetrahydrofuran/methanol (150 mL/30 mL) and stirred for 16 hours under nitrogen protection.
  • the reaction solution was poured into ice water (500 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Step 3 Compound IM-5C (10 g, 24.02 mmol) was dissolved in THF (200 mL), and BH3 ( 2 M solution in Me2S, 30.03 mL) was added at 0 °C under THF. The mixture was then reacted at 50°C for 2 hours. The mixture was quenched with MeOH (10 mL) at 0°C and stirred at 35°C for 1 hour. The mixture was concentrated to obtain a crude product.
  • Step 1 Compound IM-6B (214 g, 1.01 mol) was dissolved in methanol (2400 mL) at 25°C. Compound IM-6A (200 g, 1.01 mol) was added to the mixture. The mixture was reacted at room temperature overnight, and the reaction solution was vortexed to dryness. The crude product was slurried twice with petroleum ether (500 mL) and filtered to obtain compound IM-6C.
  • Step 1 To a solution of IM-2 (35.0 g, 141.53 mmol) in DMF (800 mL) were added compound C M-113A (2, 4-difluorobenzaldehyde, 30.17 g, 212.30 mmol, CAS 1550-35-2) and anchor carbonate (138.34 g, 424.60 mmol), and the mixture was stirred at 70.degree. C. The reaction mixture was heated under N2 protection for 16 h, cooled, filtered, and washed with DMF (100 mL). The collected filtrate was concentrated to remove most of the solvent.
  • compound C M-113A 2, 4-difluorobenzaldehyde, 30.17 g, 212.30 mmol, CAS 1550-35-2
  • anchor carbonate 138.34 g, 424.60 mmol
  • Step 2 To a solution of compound C M-113B (5.0 g, 13.54 mmol) in MeOH (160 mL) were added trimethyl orthoformate (CH(OMe)3, 21.54 g, 203.04 mmol) and p-toluenesulfonic acid monohydrate (515.0 mg, 2.71 mmol), and the mixture was heated under reflux at 70 ° C for 16 hours. Aqueous sodium carbonate solution (0.25 mol/L, 40 mL) and water (200 mL) were added, and the mixture was extracted with EA (200 mL x 2). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound CM-113Co.
  • CH(OMe)3, 21.54 g, 203.04 mmol trimethyl orthoformate
  • p-toluenesulfonic acid monohydrate 515.0 mg, 2.71 mmol
  • Step 3 To a solution of compound CM-113C (5.9 g, crude) in THF (100 mL) was added triethylamine (268.0 mg, To the reaction mixture was added 187.8 mg (2.64 mmol) of methyl parathion (2.46 g, 21.18 mmol) (20 mL) of ethyl parathion (2.64 mmol), cooled in an ice bath, and then triethylsilane (2.46 g, 21.18 mmol) was slowly added over 10 minutes at 5-8°C. The mixture was then stirred at 10-12°C for 0.5 hours, and LCMS was complete.
  • Step 4 Compound C M-113D (1.80 g, 6.40 mmol), 4-bromo-2-methoxybenzonitrile (3.40 g, 16.0 mmol, CAS: 330793-38-9), Cs 2 CO 3 (5.22 g, 16.0 mmol, Ruphos-Pd-G3 (1.07 g, 1.28 mmol, CAS: 1445085- 77-7) were added to a flask containing dry dioxane (50 mL), and the mixture was bubbled with N 2 for 5 min, and then heated at 80° C. under N 2 protection for 5 h.
  • Step 7 To a solution of compound CM-113G (200 mg, 0.54 mmol) in DCM (20 mL) was added dichloromethane (129.18 mg, 1.09 mmol). The mixture was stirred at 20°C under a N2 atmosphere for 1 hour. LCMS showed that the reaction was complete. The mixture was concentrated to give compound CM-113H without further purification. MS (ESI) m/z 387.2 [M+H] + 0.05.
  • Step 8 Compound CM-113H was added to the mixture.
  • Preparation of Stereoisomers Referring to steps 7 and 8 of this example, the reaction was carried out by replacing compound CM-113G with stereoisomer CM-113G-P1 (200 mg, 0.52 mmol) to produce compound CM-113-P1.
  • Step 10 A solution of compound C M-113-Aa (66 mg, 96.38 gmol) in DCM (2 mL)/TFA (1.48 g, 12.98 mmol, 1 mL) was stirred at 25°C under N2 for 1 hour. After the reaction, the reaction solution was directly concentrated to obtain a crude product, which was dissolved in DCM (3 mL)/DMF (1 mL). SOCl2 (42.58 mg, 357.89 gmol) was added at -78°C, and stirred for 1.5 hours. Subsequently, pyridine (56.62 mg, 715.78 gmol) was added, and stirring was continued for 1 hour.
  • CM-129-P1A CM-129-P1B
  • CM-129-P2A CM-129-P2B
  • CM-129-P2B CM-129-P2B
  • IE column 250mm*30mm*10gm
  • flow rate 25 mL/min
  • CM-129-P1 was subjected to chiral separation (IC column: 250 mm*30 mm*10 gm, mobile phase: acetonitrile/isopropanol (v/v) 50/50%, flow rate: 25 mL/min) to obtain CM-129-P1A and CM-129-P1B.
  • CM-129-P2 was subjected to chiral separation (IC column: 250 mm*30 mm*10 gm, mobile phase: acetonitrile/isopropanol (v/v) 70/30%, flow rate: 25 mL/min) to obtain CM-129-P2A and CM-129-P2B.
  • Step 2 CM-171-P1 and CM-171-P2 were prepared by referring to steps 6 and 7 of the CM-171 synthesis, replacing CM-171F with CM-171F-P1 and CM-171F-P2.
  • CM-6-A Referring to the synthesis method of compound CM-113-A in Example 7, compound CM-6-A was synthesized by using IM-2-4 instead of the reaction raw material IM-2.
  • NMR 400 MHz, DMSO-%) ⁇ 10.96 (s, 1H), 7.52-7.31 (m, 5H), 7.08-6.92 (m, 2H), 6.56-6.50 (m, 2H), 5.24-5.12 (m, 4H), 4.36-4.20 (m, 2H), 3.86 (s, 3H), 3.70-3.62 (m, 1H), 3.12-3.05 (m, 1H), 2.90-2.84 (m, 2H), 2.58-2.50 (m, 1H), 2.42-2.30 (m, 1H), 2.12-1.82 (m, 3H), 1.48-1.43 (m, 1H), 0.92 (s, 6H).
  • Example 14 Synthesis of CM-7-A ⁇ 5.17-5.19 (m, 4H), 4.70-4.91 (m, 2H), 3.70-3.62 (m, 1H), 2.92-2.84 (m, 2H), 2.68-2.58 (m, 1H), 2.44-2.31 (m, 1H), 2.10-1.78 (m, 3H), 1.55-1.48 (m, 1H), 1.22-1.18 (d, 3H), 1.06-1.00 (m, 1H), 0.45-0.40 (m, 1H)
  • Example 16 Synthesis of CM-7-A ⁇ 5.17-5.19 (m, 4H), 4.70-4.91 (m, 2H), 3.70-3.62 (m, 1H), 2.92-2.84 (m, 2H), 2.68-2.58 (m, 1H), 2.44-2.31 (m, 1H), 2.10-1.78 (m, 3H), 1.55-1.48 (m, 1H), 1.22-1.18 (d, 3H), 1.06-1.00 (m, 1H
  • CM-13-A Referring to the synthesis method of compound CM-113-A in Example 7, Compound CM-13-A can be synthesized by replacing the reaction raw material 4-bromo-2-methoxybenzyl alcohol with 5-bromo-2-methoxybenzyl alcohol (CAS: 4595-59-9).
  • CM-115 Step 1 Ph 3 P (11.93 g, 45.49 mmol) was added to a solution of compound CM-115B (5.35 g, 36.39 mmol, 4.43 mL) in THF (60 mL). The mixture was stirred for 15 minutes. DIAD (9.20 g, 45.49 mmol, 8.96 mL) in THF (60 mL) was then added to the reaction mixture at 0-5°C and stirred for 15 minutes. CM-115A (7.5 g, 30.33 mmol, IM-2) was added at 10-20°C and stirred for half an hour, followed by stirring at 20°C for 16 hours.
  • Step 2 To a solution of IPA (35 mL)/ H2O (6 mL)/DCE (17 mL) containing compound CM-115C (3.0 g, 7.97 mmol) was added NaBH4 (1.51 g, 39.85 mmol, 1.40 mL). The mixture was stirred at room temperature for 2 hours.
  • Step 3 To a solution of dioxane (35 mL) containing compound CM-115D (1600 mg, 6.50 mmol), compound CM-115E (1.97 g, 8.44 mmol), and Cs2CC>3 (79.37 mg, 243.60 gmol) was added Ruphos-Pd-G2 (326.23 mg, 389.76 mmol), and the reaction was heated at 80°C under nitrogen for 13 hours. After the reaction, the crude product obtained by concentration was purified by column chromatography (PE: EA 2: 1) to obtain compound CM-115F.
  • PE EA 2: 1
  • Step 5 To a solution of compound CM-115G (600 mg, 1.45 mmol) in THF (10 mL) were added TEA (73.60 mg, 727.36 gmol, 101.38 mmol), PdCl 2 (51.59 mg, 290.94 gmol) and triethylsilyl hydrochloride (676.60 mg, 5.82 mmol, 929.39 (iL) at 8-10 °C, and then stirred at 15°C for 1 hour under nitrogen protection. After the reaction, the reaction solution was filtered through celite and washed with MeOH (10 mL).
  • Step 8 To a solution of anhydrous toluene (0.3 mL)/THF (0.2 mL) containing compound CM-115L (63.40 mg, 243.63 gmol) was added Ph3P (85.20 mg, 324.85 gmol), DIAD (65.69 mg, 324.85 gmol, The mixture was stirred for 0.5 h, and then compound CM-115K (60 mg, 162.42 gmol) was added to the reaction mixture, followed by stirring at 40°C for 4 h.
  • Step 3 To the solution containing compound C M-118D To a solution of Cs 2 CO 3 (3.6 g, 21.88 mmol) in DMF (30 mL) were added Cs 2 CO 3 (7.17 g, 22.00 mmol) and compound C M-118E (3.32 g, 22.00 mmol), and the reaction mixture was stirred at 80° C. (2° C.) for 16 hours under nitrogen protection.
  • Example 24 Synthesis of CM-151-rac, CM-151-P1, and CM-151-P2
  • Example 25 Synthesis of CM-152-rac, CM-152-P1, and CM-152-P2
  • Step 3 The product containing compound CM-179D (1.90 g, 4-94 mmol) in HCl/EA (3 M, 10 mL)/EA (5 mL) solution was reacted at 25 ° C for 3 hours under nitrogen protection. After the reaction was completed, LCMS showed that the reaction solution was concentrated to obtain the crude product C M-179E. MS (ESI) m/z 285.0[M+H] + o Step 4: To a mixture of compound CM-179E (1.4 g, 4.37 mmol) in DMF (40 mL) were added DIEA (2.82 g, 21.83 mmol) and compound CM-179F (3.04 g, 21.83 mmol).
  • Steps 7 to 9 Referring to steps 7 to 9 of the synthesis of compound CM-118 in Example 18, compound CM-179 can be prepared from compound CM-179J.
  • a DMF solution of compound CM-198A (11.35 g, 52.00 mmol) was added dropwise to the reaction solution, maintaining the temperature below -70°C. Stirring was continued for 30 minutes.
  • a THF solution (0.5 mL/mmol) of compound CM-198B (13.15 g, 40 mmol) was then added dropwise to the reaction solution. The reaction solution was then warmed to -60°C. After completion of the reaction, the mixture was quenched with saturated chromium chloride solution and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • Step 7 At 110°C, a solution of compound CM-198K (380 mg, 737.27 gmol), (tributyltin)methanol (710.18 mg, 2.21 mmol), and Pd(PPh3)2Cl2 (51.75 mg, 73.73 gmol) in dioxane (15 mL) was stirred for 24 hours under a nitrogen atmosphere. After completion of the reaction, the mixture was quenched with water and extracted with dichloromethane (20 mL x 3).
  • methylsulfonyl chloride 39.28 mg, 342.95 gmol, 26.60 ⁇ L was added dropwise to a solution of compound CM-198L (160 mg, 342.95 gmol) and triethylamine (34.70 mg, 342.95 gmol, 47.80 ⁇ L) in dichloromethane (3 mL), and stirred at 25°C for 0.5 h. After the reaction was complete, water was added to quench the mixture, and the mixture was extracted with dichloromethane (1 mL x 3). The organic phase was washed with saturated brine (3 mL) and dried over anhydrous sodium sulfate.
  • Step 9 Under a nitrogen atmosphere at 25°C, anhydrous methyl carbonate (284.16 mg, 872.14 gmol) was added to compound CM-198M (190 A solution of 100 mg, 348.86 gmol) and compound CM-198N (108.95 mg, 418.63 gmol) in dimethylformamide (10 mL) was stirred at 50°C for 16 hours. After completion of the reaction, the mixture was quenched with water and extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate.
  • CM-198-P1 can be prepared from CM-198L-P1.
  • CM-198-P2 was prepared from CM-198L-P2.
  • CM-201 Step 1 At 0. Under a nitrogen atmosphere (25°C), sodium borohydride (8.91 g, 235.47 mmol) was added portionwise to a stirred solution of compound CM-201A (10.6 g, 47.09 mmol) in ethanol (140 mL), and the reaction mixture was stirred at 25°C for 1 hour. After the reaction was complete, the reaction mixture was quenched by adding water and extracted with ethyl acetate (100 mL x 3).
  • Step 2 Under a nitrogen atmosphere (25°C), p-toluenesulfonic acid (834.10 mg, 4.84 mmol) was added portionwise to a stirred solution of compound CM-201B (11 g, 48.44 The reaction mixture was stirred at 85°C for 4 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (50 mL x 3).
  • Step 3 Under a 0.2% nitrogen atmosphere, m-chloroperbenzoic acid (9.90 g, 57.39 mmol) was added dropwise to a stirred solution of compound CM-201C (10 g, 47.83 mmol) and sodium carbonate (10.14 g, 95.66 mmol) in water (200 mL) and dichloromethane (200 mL). The reaction mixture was stirred at 25°C for 1 hour.
  • Step 4 Under a 25°C (24°C) nitrogen atmosphere, triethylamine (1.34 g, 13.21 mmol, 1.84 mL) was added portionwise to a stirred solution of compound CM-201D (3 g, 13.21 mmol) and compound CM-201E (2.71 g, 13.21 mmol) in acetonitrile (200 mL). The reaction mixture was stirred at 85°C for 16 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (150 mL x 3). The combined organic phases were washed with saturated brine (150 mL) and dried over anhydrous sodium sulfate.
  • Step 5 Under nitrogen atmosphere at 0°C, TBSOTf (2.15 g, 8.13 mmol, 1.87 mL) was added portionwise to a solution of compound CM-201F (1.75 g, 4.07 mmol) and 2,6-dimethylpyridine (1.31 g, 12.20 mmol, 1.42 mL) in dichloromethane (20 mL). The reaction mixture was stirred at 25.
  • Step 6 Under a nitrogen atmosphere, a stirred solution of compound CM-201G (2.1 g, 3.86 mmol) with (tributyltin)methanol (3.55 g, 11.57 mmol) and Pd Ruphos G3 (483.78 mg, 578.44 gmol) in dioxane (80 mL) was stirred at 110°C for 24 hours. After the reaction was complete, the reaction mixture was quenched with water and extracted with dichloromethane (80 mL x 3). The combined organic phases were washed with saturated brine (80 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • Steps 7-9 Referring to steps 4-6 of the synthesis of compound CM-177 in Example 27, compound CM-201H was prepared to obtain compound CM-201.
  • CM-206A (3.5 g, 8.81 mmol) was dissolved in DCM (20 mL), and HCl-dioxane (20 mL, 2M) was added. The mixture was stirred at 20°C for 3 h. LCMS showed that the reaction was complete, and the mixture was concentrated to give CM-206B. MS (ESI) m/z 297.0, 299.0 [M+H] + .
  • Step 2 Compound CM-206B (2.5 g, 8.41 mmol) and 3, 4-difluorobenzonitrile (1.17 g, 8.41 mmol) were dissolved in DMF (80 mL), and DIEA (5.43 g, 42.1 mmol) was added. The mixture was stirred at 50°C for 1 h. The reaction was continued for 16 hours at 400 °C. The crude product was concentrated and purified by silica gel column chromatography (PE:EA 3:1) to give CM-206C.
  • PE:EA 3:1 silica gel column chromatography
  • Step 3 A mixture of compound CM-206C (1.5 g, 3.60 mmol), (tributyltinyl)methanol (3.47 g, 10.81 mmol), and Ruphos Pd G3 (241.40 mg, 288.28 gmol) in dioxane (30 mL) was heated at 85°C under N2 protection for 16 hours. The mixture was poured into water (50 mL), extracted with EA (60 mL x 3), washed with brine (100 mL), dried over anhydrous Na2SO4 , and concentrated to obtain a crude product. Purification by silica gel column chromatography (PE:EA 10:1 to 2:1) gave CM-206D0.
  • Step 4 To a suspension of compound CM-206E (150.00 mg, 576.38 gmol) in toluene (1.5 mL) and THF (1.5 mL) was added triphenylphosphine (302.4 mg, 1.15 mmol). A solution of diisopropyl azodicarboxylate (233.10 mg, 1.15 mol) in THF (1.5 mL) was added under ice-cooling, followed by stirring for 0.5 hour. CM-206D (254.11 mg, 691.66 gmol) was then added, and the mixture was stirred at 35°C for 20 hours.
  • CM-206 was concentrated and purified by preparative liquid chromatography (5-60% A:ACN, B: H2O (0.1% NH4OAc )) to afford CM-206 as a white solid.
  • reaction mixture was concentrated to afford the intermediate.
  • SOCl2 (0.65 g, 6.11 mmol) was added to a solution of the intermediate in DCM/DMF (9 mL/3 mL) at -78°C under nitrogen.
  • the reaction mixture was stirred at -78°C for 1.5 hours.
  • Pyrrolidone (0.97 g, 12.22 mmol) was slowly added, and the reaction mixture was stirred at -78°C for 1 hour.
  • the reaction mixture was quenched with water (10 mL), adjusted to pH 8 by adding aqueous NaHCO3, and extracted with dichloromethane (50 mL x 3).
  • CM-132, CM-132-P1, and CM-132-P2 Synthesis of CM-132 Compound CM-148 (1.0 g, 1.72 mmol) was dissolved in THF/MeOH (30 mL/6 mL), and LiBHq (37.46 mg, 1.72 mmol) was added to the reaction flask at -78 °C. The mixture was stirred at 4°C for 1 hour. Saturated NH 4 Cl (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL ⁇ 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated.
  • the reaction mixture was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous Na2SO4 , filtered, and the filtrate was concentrated.
  • the reaction mixture was poured into ice water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated.
  • CM-160-P2 X H NMR (400 MHz, DMSO-d) d 10.96 (s, 1H), 7.68-7.61 (m, 1H), 7.58-7.46 (m, 3H),
  • CM-189-P2 2H
  • CM-190 Synthesis of CM-190-P1, CM-190-P2 Synthesis of compound CM-190 Step 1: Sodium borohydride (430.67 mg, 11.33 mmol) was added to a stirred solution of compound IM-6-2 (4 g, 10.30 mmol) in methanol (9 mL) and tetrahydrofuran (45 mL) at -78°C under nitrogen protection. (2) The reaction was stirred for 1 hour. The reaction solution was quenched by adding chromium chloride solution at -78°C. It was then extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered.
  • Step 2 Under nitrogen protection, tert-butyldimethylsilyl chloride (1.20 g, 14.61 mmol) was added to a stirred solution of compound CM-190A (3.8 g, 9.25 mmol) and imidazole (1.66 g, 24.34 mmol) in dichloroethane (30 mL). The reaction solution was stirred at 100 °C under nitrogen protection for 16 hours. The reaction solution was quenched by adding water and extracted with dichloromethane.
  • Step 4 Under nitrogen protection, MsCl (1.43 g, 12.51 mmol) was added dropwise to a stirred solution of compound CM-190C (1.9 g, 3.96 mmol) and triethylamine (25.02 mmol, 3.49 mL) in dichloromethane (20 mL) in VC. The reaction solution was stirred at 0.8°C for 30 min. After the reaction was complete, the reaction solution was quenched with water and extracted with dichloromethane. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product CM-190D was used directly in the next step.
  • Step 5 Under nitrogen protection at 25°C, anhydrous sodium carbonate (3.63 g, 11.13 mmol) was added to a stirred solution of compound CM-190D (2.2 g, 3.71 mmol) and IM-1 (1.24 g, 3.71 mmol) in dimethyl sulfoxide (20 mL). The reaction mixture was stirred at 25°C under nitrogen protection for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered.
  • CM-190-P1 and CM-190-P2 can be prepared from CM-190E-P1 and CM-190E-P2, respectively.
  • CM-134-P1 can be prepared from CM-134F-P1 by referring to steps 5 to 7 of the synthesis of compound CM-190 in Example 43. 134F-P2 was used to prepare CM-134-P2o
  • CM-174-P1 E NMR (400 MHz, DMSO-%) S 10.95 (s, IH), 7.59-7.48 (m, 3H), 7.42-7.32 (m, 2H), 7.25-7.15 (m, 2H), 6.93-6.86 (m, 1H), 6.83-6.77 (m, 1H), 5.31-5.21 (m, 2H), 5.13-5.06 (m, 1H), 4.70-4.61 (m, 1H), 4.41-4.34 (m, 1H), 4.25-4.18 (m, 1H), 3.82-3.68 (m, 2H), 3.50-3.45 (m, 1H), 3.37-3.34 (m, 4H), 2.94- 2.84 (m, 1H), 2.58-2.51 (m, 4H), 2.46-2.43 (m, 2H), 2.01-1.90 (m, 1H).
  • CM-175-P1 E NMR (400 MHz, DMSO-HCl). ⁇ 10.95 (s, 1H), 7.58-7.48 (m, 2H), 7.43-7.32 (m, 3H),
  • CM-175-P2 E NMR (400 MHz, DMSO-%) S 10.95 (s, IH), 7.58-7.49 (m, 2H), 7.43-7.32 (m, 3H), 7.25-7.17 (m, 2H), 6.56-6.48 (m, 2H), 5.30-5.22 (m, 2H), 5.13-5.07 (m, IH), 4.70-4.60 (m, IH), 4.41-4.35 (m, IH), 4.25-4.18 (m, IH), 3.84 (s, 3H), 3.81-3.65 (m, 2H), 3.52-3.46 (m, IH), 3.32-3.26 (m, 4H), 2.94-2.85 (m, 1H), 2.61-2.51 (m, 4H), 2.45-2.38 (m, 2H), 1.99-1.92 (m, 1H).
  • Example 50 Synthesis of CM-196
  • CM-196 was prepared by replacing the starting material with IM-4-5.
  • MS (ESI) m/z 599.3 [M+H]+, de: 98.17 %
  • Example 51 Synthesis of CM-197 Referring to steps 2 to 7 of the synthesis of compound CM-190 in Example 43, replace the starting material with IM-4-6 to prepare CM-197.
  • CM-164B The organic phase was dried, filtered, and concentrated to yield CM-164B, which was used directly in the next step.
  • Step 2 A solution of compound CM-164C (5 g, 22.00 mmol) in HCl (5 M, 20 mL)/dioxane (50 mL) was stirred at 25 °C under nitrogen for 1 hour. After the reaction, the filtrate was concentrated to obtain the crude product CM-164D, which was used directly in the next step.
  • Step 3 Compound CM-164E and anchor carbonate (7.17 g, 22.00 mmol) were added to a solution of compound CM-164D in DMF (30 mL). The mixture was then stirred at 80 °C under nitrogen for 16 hours.
  • Step 4 At -78°C, n-BuLi (892.70 mg, 13.94 mmol, 1.76 mL) was added to THF (50 mL) containing compound CM-164F (1.74 g, 6.97 mmol). After stirring for 2 hours, a solution of compound CM-164B (2.7 g, 10.45 mmol) in THF (60 mL) was added, and stirring was continued at -78°C for 2 hours.
  • CM-164 can be prepared from CM-164H by referring to Steps 4 to 6 in the synthesis of Compound CM-190 in Example 43.
  • PE:EA 2:1, 600 mL
  • Example 55 Synthesis of CM-193, CM-193-P1, and CM-193-P2 Referring to steps 2 to 7 of the synthesis of compound CM-190 in Example 43, the starting material was replaced with IM-5-1 to prepare CM-193. Referring to the synthesis of CM-134-P1 and CM-134-P2 in Example 45, the corresponding intermediates were subjected to chiral resolution and subsequent reactions to obtain the stereoisomers CM-193-P1 and CM-193-P2.
  • CM-193-P1 2H), 7.31-7.28 (m, 1H), 7.14-7.07 (m, 2H), 5.24 (s, 2H), 5.13-5.08 (m, 1H), 4.62-4.60 (m, 1H), 4.40-4.36 (m, 1H), 4.24-4.20 (m, 1H), 4.05-3.90 (m, ⁇ 5.77-5.64 (m, 2H), 1.49-2.62 (m, 1H), 1.23-1.47 (m, 2H), 1.11-1.99 (m, 1H).
  • CM -193-P2 (m, 2H), 7.31-7.28 (m, 1H), 7.14-7.07 (m, 2H), 5.24 (s, 2H), 5.13-5.08 (m, 1H), 4.62-4.60 (m, 1H), 4.40-4.36 (m, 1H), 4.24-4.20 (m, 1H), 4.05-3.90 (m, 2H), 3.72-3.69 (m, 2H), 2.95- 2.74 (m, 3H), 2.58-2.53 (m, 2H), 2.47-2.39 (m, 1H), 1.98-1.95 (m, 3H), 1.36-1.22 (m, 2H), 1.09-0.99 (m, 1H).
  • CM-183E can be prepared from CM-183A by referring to Steps 3-6 of the synthesis of compound CM-190 in Example 43. MS (ESI) m/z 623.2 [M+H] + . Step 6. To a solution of compound C M-183E (300.00 mg, 0.482 mmol) in THF (36 mL) was added Pd/C (150.00 mg, 1.24 mmol). The mixture was stirred at 25° C. under a balloon of H2 for 2.5 hours. The mixture was filtered through Celite and washed with THF (30 mL). The filtrate was concentrated under reduced pressure.
  • Example 60 Synthesis of CM-186
  • CM-186 Referring to the synthesis procedure of compound CM-183 in Example 57, the corresponding starting material was replaced with IM-4-4 to obtain CM-186.
  • Chiral HPLC analysis conditions: Column: 1H, Column: Size: 250mm*4.6mm 5um, method: MeOH-EtOH-DEA 50-50-0.1, flow rate: 1mL/min, retention time: 6.564, CM-188 hydrochloride was prepared by referring to the synthesis procedure of compound CM-183 in Example 57, replacing the corresponding starting material with IM-4-6.
  • Step 2 Compound CM-180A (19 g, 55.82 mmol) and di-tert-butyl dicarbonate (18.25 g, 83.73 mmol) were dissolved in tetrahydrofuran (130 mL) and water (130 mL). The reaction was allowed to proceed at 25 °C under nitrogen for 3 hours. The reaction mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried.
  • Example 67 Synthesis of CM-182 CM-182 hydrochloride was prepared by referring to the synthesis procedure of compound CM-180 in Example 65, replacing the corresponding starting material with IM-7-4.
  • CM-163-P1 and CM-163-P2 Referring to the synthesis procedures of compounds CM-180-P 1 and CM-180-P 2 in Example 65, the corresponding starting materials were replaced with IM-7-1, the corresponding intermediates were resolved, and subsequent reactions were carried out to prepare CM-163-P1 hydrochloride and CM-163-P2 hydrochloride.
  • the ⁇ -values (nm) were 0.044 (m, 1H), 0.081 (m, 2H), 0.096 (m, 3H), 1.25 (m, 2H), 1.44 (m, 1H), 0.081 (m, 3H), 0.096 (m, 2H), 0.13 (m, 4H), 1.2 (m, 2H).
  • Example 70 Synthesis of CM-204, CM-204-P1, and CM-204-P2
  • Compound CM-180 (30 mg, 51.49 gmol) was dissolved in hexafluoroisopropanol (2.0 mL), and a solution of methyl trifluoromethanesulfonate (18.59 mg, 113.28 gmol) in hexafluoroisopropanol (0.5 mL) was added. The reaction mixture was then stirred at 25°C for 16 hours. The reaction mixture was concentrated, and water (5 mL) was added to the residue. The mixture was extracted with ethyl acetate (20 ml x 3).
  • CM-204 hydrochloride can be prepared from CM-180-P1
  • CM-204-P2 hydrochloride can be prepared from CM-180-P2.
  • CM-204-P1 E NMR (400 MHz, DMSO-%).
  • Step 2 Iron powder (5.07 g, 90.82 mmol) was added to a solution of compound CM-211B (3.3 g, 9.08 mmol) and NH 4 Cl (2.43 g, 45.41 mmol) in EtOH (50 mL) and H 2 O (15 mL). The mixture was stirred at 75°C under nitrogen protection. (2) Heating for 1 hour.
  • PE/EA 1:2
  • Step 4 PhSO3H (1.26 g, 7.94 mmol) was added to a solution of compound CM-211D (1.0 g, 1.32 mmol) in ACN (40 mL), and the mixture was heated at 90°C (2°F) for 3 h under nitrogen. The mixture was cooled to room temperature and concentrated under reduced pressure to afford the crude product. The residue was purified by Prep-HPLC (5-60% A. A: ACN, B: H2O (0.001 M aq. HCl) to afford the hydrochloride salt of CM-211D as a white solid.
  • Step 3 Compound CM-212D (1 g, 1.30 mmol) was dissolved in ACN (50 mL), and benzenesulfonic acid (410.39 mg, 2.59 mmol, 315.69 mmol) was added. The reaction solution was stirred at 85°C under nitrogen protection. (2) The reaction was stirred for 3 hours. After the reaction was completed, LCMS showed that the reaction solution was concentrated and the crude product was dissolved in DMF (20 mL).
  • Step 2 To a solution of compound C M-213A (5 g, 25.89 mmol) and (4S)-4,5-diamino-5-oxo-pentanoic acid tert-butyl ester (6.18 g, 25.89 mmol, CAS 108607-02-9) in DMF (50 mL) was added CDI (7.45 g, 51.78 mmol), and the mixture was stirred at 25 °C under a tantalum atmosphere for 3 h.
  • Triethylamine (5.36 g, 53.00 mmol, 7.39 mL) was added at -78 °C and stirred for 1 hour. The reaction was quenched with H2O (10 mL) at -60 °C, and then slowly warmed to room temperature, extracted with DCM (500 mL x 2), washed with H2O (500 mL) and brine (500 mL x 2), and then concentrated to obtain a crude product. The crude product was purified by Prep-HPLC. (5-60% A, A: ACN, B: H 2 O) was purified to afford CM-213C as a yellow solid. MS (ESI) m/z 304.1 [M+H] + .
  • Step 4 Compound CM-213C (2 g, 6.60 mmol) was dissolved in DMF (10 mL) and THF (100 mL), and Pd/C (801.08 mg, 6.60 mol) was added. The mixture was stirred at 20° C. under a H 2 (50 psi) atmosphere for 16 hours. After completion of the reaction, the reaction mixture was filtered through celite, and the filtered product was concentrated in vacuo to afford CM-213D as a yellow solid. MS (ESI) m/z 274.1 [M+H] + .
  • Step 5 Compounds CM-213D (500 mg, 1.83 mmol) and CM-213E ( To a solution of 1.04 g, 2.38 mmol) in DMF (15 mL) was added TMSC1 (596.17 mg, 5.49 mmol) dropwise. The mixture was then stirred at 20 ° C. for 1 hour, and then BH 3 -THF (1 M, 2.74 mL) was added dropwise at 0° C. for 20 minutes. The mixture was stirred at 20° C. overnight.
  • Step 6 Compound C M-213F (450 To a solution of 1,4-dioxane (10 mL) of 1,4-dioxane (4 M, 3.50 mL) was added HCl/dioxane (4 M, 3.50 mL), and the mixture was stirred at 20° C. for 2 hours. The reaction solution was concentrated, and the residue was purified by Prep-HPLC (5-60% A. A: ACN, B: 0.1% HCl) to obtain the hydrochloride salt of CM-213.
  • CM-217 Step 1 Tetraethyl titanate (8.75 g, 38.34 mmol, 8.04 mL) was added to 1 M-6-3 (8.0 g, 19.17 mmol) and CM-217A (2.79 g, 23.01 mmol) in THF (160 mL), and the mixture was stirred at 70. (2) refluxed for 16 hours. The reaction was cooled and quenched by the addition of H2O (100 mL), filtered through celite, and the filtrate was extracted with EA (100 mL x 2 ).
  • CM-217 hydrochloride can be prepared from CM-217D according to Steps 3-5 of the synthesis of compound CM-180 in Example 65.
  • Step 4 To a solution of compound CM-222C (320 mg, 739.98 gmol) and compound IM-8 (374.69 mg, 739.98 gmol) in dioxane (6 mL)/water (0.2 mL) were added K3PO4 (314.15 mg, 1.48 mmol), Pd2(dba)3 (101.64 mg, 111.00 gmol) and P(o-Tol) 3 (33.78 mg, 111.00 gmol). The reaction solution was stirred at 110°C under nitrogen protection. (2) The reaction was allowed to proceed for 1 hour.
  • CM-222-P1A CM-222-P1B
  • CM-222-P2A CM-222-P2B
  • CM-222-P2B CM-222-P2B
  • chiral separation chromatographic column: IC, 250mm*4.6mm 5gm, conditions: Hex-IPA-DEA-90-10-0.1, 1cm
  • Step 1 to Step 3 Referring to the synthesis process of Steps 1 to 3 of Compound CM-190 in Example 43, CM-224C can be prepared from Compound IM-6-6.
  • CM-224E-PL can be prepared from CM-224C-P1
  • CM-224E-P2 can be prepared from CM-224C-P2, following the synthetic procedures of Steps 3-4 of Example 76 for the synthesis of compound CM-222.
  • Step 6 Referring to the synthesis process of Step 5 in the synthesis of compound CM-222 in Example 76, the corresponding stereoisomer products can be obtained from CM-224E-P1A, CM-224E-P1B, CM-224E-P2A and CM-224E-P2B.
  • C M-224-P1Ao was obtained from C M-224E-P1A.
  • CM-224-P2A was obtained from CM-224E-P2A.
  • CM-224-P2B was obtained from CM-224E-P2B.
  • Example 78 Synthesis of CM-225-P1A, CM-225-P1B, CM-225-P2A, and CM-225-P2B Steps 1-2: CM-225Bo was prepared from compound IM-7-6 by referring to Steps 1-2 of the synthesis of compound CM-180 in Example 65. MS (ESI) m/z 287.0, 289.0 [M+H] + .
  • CM-225D-PL can be prepared from CM-225B-P1
  • CM-225D-P2 can be prepared from CM-225B-P2.
  • CM-225-P1B hydrochloride was obtained from CM-225D-P1B.
  • NMR 400 MHz, DMSO-J 6 ) d 11.13 (s, 1H), 8.50 (s, 3H), 8.38-8.36 (d, 8.4
  • CM-225-P2A hydrochloride was obtained from CM-225D-P2A.
  • X H NMR 400 MHz, DMSO-J 6 ) 11.13 (s, 1H), 8.51 (s, 3H), 8.38-8.36 (d, 8.0
  • CM-225-P2B hydrochloride was obtained from CM-225D-P2B.
  • MS (ESI) m/z 636.2 [M+H] + .
  • Example 81 Synthesis of CM-228-P1A, CM-228-P1B, CM-228-P2A, and CM-228-P2B
  • CM-225-P1A, CM-225-P1B, CM-225-P2A, and CM-225-P2B Referring to the synthesis process of compounds CM-225-P1A, CM-225-P1B, CM-225-P2A, and CM-225-P2B in Example 78, replacing the starting material with IM-7-1, CM-228-P1A hydrochloride, CM-228-P1B hydrochloride, CM-228-P2A hydrochloride, and CM-228-P2B hydrochloride can be prepared.
  • CM-228-P1A 97.11 % de
  • Example 82 Synthesis of CM-229-P1A, CM-229-P1B, CM-229-P2A, and CM-229-P2B Referring to the synthesis process of compounds CM-224-P1A, CM-224-P1B, CM-224-P2A, and CM-224-P2B in Example 77, CM-229-P1A, CM-229-P1B, CM-229-P2A, and CM-229-P2B can be prepared by replacing the starting material with IM-6-1.
  • CM-229-P1A 99.24% de.
  • PE:EA 3:1
  • Step 8 At zero temperature, TEA (847.67 mg, 8.38 mmol, 1.17 mL) and MsCl (636.65 mg, 5.58 mmol) were added to a solution of compound I (1.3 g, 2.79 mmol) in DCM (30 mL). The reaction was carried out at room temperature under nitrogen protection for 1 hour. After the reaction, the reaction solution was quenched by adding water (200 mL) and extracted with EA (40 mL*4). The organic phases were combined, dried, filtered, and concentrated to afford crude product K, which was used directly in the next step. MS (ESI) m/z 544.2 [M+H]+.
  • Step 11 Compound M-P1 (40.00 mg, 51.16 gmol) was dissolved in ACN (2 mL), and benzenesulfonic acid (24.28 mg, 153.47 gmol) was added. The reaction was incubated at 85°C under nitrogen for 3 hours.
  • Step 5 To a solution of molten salt (50 mL) containing compound 6 (2.7 g, 7.56 mmol) at zero temperature was added NaBH3CN (950.03 mg, 15.12 mmol). The reaction was allowed to proceed at room temperature under nitrogen for 2 hours. After the reaction, the reaction mixture was poured into water (500 mL) for quenching, followed by multiple extractions with ethyl acetate (200 mL x 3).
  • ACN-H2O 5-95%, aqueous phase: 1/1000 formic acid aqueous solution
  • Step 3 Under 25°C atmospheric pressure, compound D (14.0 g, 41.18 mmol) was dissolved in dichloromethane (50 mL). Triethylamine (8.32 g, 82.36 mmol) and compound E (11.49 g, 61.77 mmol) were added and stirred at 25°C for 2 hours.
  • Step 8 Compound K (700 mg, 1.24 mmol) was dissolved in 1,4-dioxane (5 mL) and water (2 mL), and 1,1-bis(diphenylphosphinothiazolinone)ferrochloride (181.5 mg, 0.248 mmol), compound L (697.6 mg, 1.61 mmol) and potassium phosphonate (788.6 mg, 3.72 mmol). The reaction solution was stirred at 90 °C under nitrogen protection for 2 hours. After the reaction was complete, the filtrate was extracted with ethyl acetate (50 mL*3).
  • Step 1 Under 25°C atmospheric pressure, compound 1 (3.2 g, 10.5 mmol), imidazole (1.4 g, 21.1 mmol), and TBSC1 (1.9 g, 12.6 mmol) were added to dichloromethane (25 mL). The reaction solution was stirred at 20°C for 5 hours. After the reaction was complete, the reaction solution was diluted with ice water (10 mL) and extracted with ethyl acetate (20 mL x 2). The organic phases were combined and concentrated to obtain a crude product. The crude product was then purified by silica gel column chromatography to obtain compound 2 (3.2 g, 7.6 mmol, yield: 73%) as a yellow oil.
  • Example 87 Synthesis of CM-244 Step 1: At 0. (2 Under nitrogen, TBSOTf (3.98 g, 15.05 mmol) was added dropwise to a solution of compound A (1.36 g, 5.02 mmol) and triethylamine (2.54 g, 25.08 mmol, 3.50 mL) in dichloromethane (10 mL), and stirred at 0 ° C for 30 minutes. After the reaction was complete, water was added to quench the reaction, and dichloromethane (50 mL * 3) was used for extraction. The organic phase was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • Step 2 Tetrakistriphenylphosphane (382.58 mg, 331.08 gmol) was added to compound B (1.28 g, 3.31 mmol) and (tributyltin)methanol (2.13 g, 6.62 mmol) in dioxane (20 mL) were stirred at 90°C for 16 hours. After the reaction was complete, the mixture was cooled, quenched with water, and extracted with dichloromethane (50 mL*3). The organic phase was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • Step 5 To DCM (12 mL) containing compound 6 (300 mg, 853.35 gmol) was added triethylamine (259.05 mg, 2.56 mmol, 356.82 ⁇ L) and methanesulfonyl chloride (195.51 mg, 1.71 mmol, 132.37 ⁇ L) under nitrogen protection at room temperature for 2 hours. After the reaction, the reaction mixture was poured into water (150 mL) for quenching, followed by multiple extractions with dichloromethane (40 mL*4). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product 7.
  • ACN-H2O 5-95%, aqueous phase: 1/1000 trifluoroacetic acid aqueous solution
  • Step 2 Under 25°C atmospheric pressure, anhydrous sodium carbonate (308.28 mg, 946.18 gmol) was added to a solution of compound B (180 mg, 315.39 gmol) and compound C (116.00 mg, 346.93 gmol) in DMF (5 mL). The mixture was stirred at 25°C for 2 hours. After completion of the reaction, water was added to quench the mixture, and the mixture was extracted with dichloromethane (5 mL x 3). The organic phase was washed with saturated brine (5 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • Step 2 To a solution of compound 2 (470 mg, 1.65 mmol) and tert-butoxyacetic acid (218 mg, 1.65 mmol) in dichloromethane (5 mL) were added HATU (760 g, 2.0 mmol) and triethylamine (330 mg, 3.3 mmol) at room temperature. The mixture was stirred at 20 °C for 10 hours. After the reaction was complete, the reactant was concentrated, ice water was added, and then extracted with ethyl acetate (50 mL x 2).
  • Step 6 TMSOTF (2.11 g, 9.52 mmol) was added to DMF (10 mL) containing compound H (260 mg, 951.53 gmol) and compound G (502.66 mg, 1.19 mmol) at 0°C. The mixture was reacted at room temperature for 1 hour under nitrogen protection. BH3.THF (1 M, 4.76 mL), and stirred again for 1 hour. After the reaction was completed, the reaction solution was quenched by adding ice water (100 mL), and extracted with ethyl acetate (30 mL*4) for multiple times. The organic phases were combined, dried, filtered, and concentrated. The crude product was dissolved in DMF.
  • CM-002 Step 1 Under a -78°C atmosphere, n-butyllithium (4.48 g, 70.00 mmol, 2.5 M) was added dropwise to a solution of compound A (21.06 g, 70 mmol) in tetrahydrofuran (210 mL). The mixture was stirred at -78°C for 15 minutes.
  • Step 8 Under a 0.2% nitrogen atmosphere, a solution of hydrochloric acid in dioxane (4.5 mL, 2 M) was added dropwise to a solution of compound K (60 mg, 90.25 gmol) in dioxane (0.5 mL). After the reaction was complete, the reaction solution was concentrated to obtain the crude product, which was then purified by preparative HPLC (5-95% A.
  • EAinPE 5%
  • Step 2 Under nitrogen atmosphere at 25°C, compound C (4.0 g, 19.88 mmol) was dissolved in dichloromethane (20 mL) solution, and triethylamine (8.03 g, 79.52 mmol), compound D (2.53 g, 25.84 mmol) and N,N,N',N'-tetramethyl-0-(7-azabenzotriazole-1-yl)phosphine hexafluorophosphate (11.33 g, 29.82 mmol) were added and stirred at 25°C for 5 hours. After the reaction was complete, water was added to quench the mixture and the mixture was extracted with ethyl acetate (50 mL*3).
  • Step 10 Compound N (122 mg, 0.16 mmol) was dissolved in DCM (3 mL) and triethylamine (3 mL) was added. The reaction mixture was stirred at 25 °C under nitrogen for 3 days. Trifluoroacetic acid (2 mL) was added to the reaction mixture and concentrated to obtain a crude product. The crude product was purified using a C18 column (5-95% ACN in water (0.1% TFA)) to obtain the trifluoroacetate salt of compound C M-003.
  • a cell suspension at a density of 100,000 cells/mL was plated into the corresponding wells of a 384-well plate (4,000 cells/well) to ensure that the control cells remained in the linear growth phase during the five-day experimental period.
  • the 384-well plates with cells were incubated in a 37°C, 5% CO2 incubator for 24 hours.
  • the compound was prepared in DMSO (Sigma, catalog number 276855-1L) to a 10 mM stock solution. The compound stock solution was then further diluted in DMSO to 20 nM and 20 nM working solutions.
  • MM.1S cells Drug treatment of MM.1S cells began with a maximum concentration of 100 nM and was then performed in triplicate over a 10-point, 4-fold serial dilution. Nanoliter volumes of compound solution were added to the corresponding wells of the 384-well plates using an HPD300 micropipette dispenser (Tecan) via contactless dispensing according to the desired concentration. The final DMSO concentration was 0.5%. After drug administration, the 384-well plates were incubated in a 37°C, 5% CHCl incubator for 120 hours. After five days of drug treatment, 25 ⁇ L of CTG reagent (Promega, catalog number G7573) was added to each well and shaken on a plate shaker for 10 minutes to ensure complete cell lysis.
  • CTG reagent Promega, catalog number G7573
  • MM.1S Cell Proliferation Inhibition Results “D” indicates an IC50 value of 0.01 nM, “E” indicates an IC50 value of ⁇ 0.01 nM, and “C50” indicates an IC50 value of ⁇ 0.04 nM.
  • the results showed that, with the exception of CM-115, the compounds in this application all had IC50 values of ⁇ 1 nM, demonstrating excellent inhibitory activity against MM.1S cell proliferation, surpassing the activity of the control substance, lenalidomide. Some compounds also achieved activity levels exceeding picomolar (pM), significantly exceeding that of the control substance.
  • pM picomolar
  • Test Example 2 Aiolos Degradation Activity Assay Method: The degradation of Aiolos protein by the compounds was tested using a Hibit-labeled IKZF3 stably transfected cell line. A Hibit tag was added to exogenous IKZF3 and then transformed into OCI-LY10 cells (Nanjing Kebai, CBP60558) to construct the stable transgenic line OCI-LY10-IKZF3-Hibit. OCI-LY10-IKZF3-Hibit cells in the logarithmic growth phase were resuspended in IMDM + 20% FBS + 1 g/mL Pure Medium. Cell viability was determined to be >90% using an automated cell counter (ViCell XR).
  • ViCell XR automated cell counter
  • Cells were plated in 96-well plates. 45 ⁇ L of cell suspension was plated per well at a cell density of 20,000 cells/well. The plated 96-well plates were incubated at 37°C in a 5% CO2 incubator. On the day of dosing, the compound was prepared into a 10 mM stock solution in DMSO. The stock solution was first diluted 100-fold in DMSO, and a series of compound dilutions were further diluted 100-fold in cell culture medium to obtain working solutions. 5 ⁇ L of compound working solution was added to each well of the cell culture plate, starting with a final drug concentration of 100 nM. The solution was then diluted in a 5-fold gradient over eight concentration points.
  • the 96-well plate was incubated at 37°C in a 5% CO2 incubator for 24 hours.
  • the assay was then performed using the Promega Nano-Gio® HiBiT Lytic Detection System (Promega, N3040).
  • the cell plate was removed and equilibrated at room temperature. 0.50 ⁇ L of Hibit detection reagent was added to each well.
  • the sample was shaken in the dark for 10 minutes and assayed using a chemiluminescence microplate reader (LumiStation 1800).

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Abstract

La présente invention concerne un composé d'isoindoline substitué, un procédé de préparation, une composition pharmaceutique et une utilisation. La présente invention concerne un composé d'isoindoline tel que représenté par la formule générale (XI), ou un stéréoisomère, un tautomère ou un sel pharmaceutiquement acceptable de celui-ci. Le composé d'isoindoline de la présente invention peut cibler et réguler spécifiquement une grande diversité de protéines par liaison au céréblon, ce qui permet de traiter efficacement des maladies associées telles que le cancer.
PCT/CN2025/083791 2024-03-21 2025-03-20 Composé d'isoindoline substitué, procédé de préparation, composition pharmaceutique et utilisation Pending WO2025195464A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102822165A (zh) * 2010-02-11 2012-12-12 细胞基因公司 芳基甲氧基异吲哚啉衍生物和包括其的组合物及它们的使用方法
CN104837491A (zh) * 2012-08-09 2015-08-12 细胞基因公司 利用3-(4-((4-(吗啉代甲基)苯甲基)氧基)-1-氧代异二氢吲哚-2-基)哌啶-2,6-二酮治疗癌症的方法
CN105566290A (zh) * 2014-10-30 2016-05-11 康朴生物医药技术（上海）有限公司 异吲哚啉衍生物、其中间体、制备方法、药物组合物及应用
CN106551934A (zh) * 2015-09-29 2017-04-05 康朴生物医药技术（上海）有限公司 一种药物组合物及其应用
WO2018108147A1 (fr) * 2016-12-16 2018-06-21 康朴生物医药技术（上海）有限公司 Composition, son application et procédé de traitement
CN112839658A (zh) * 2018-10-01 2021-05-25 细胞基因公司 用于治疗癌症的组合疗法
WO2022007659A1 (fr) * 2020-07-06 2022-01-13 北京诺诚健华医药科技有限公司 Immunomodulateur hétérocyclique

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102822165A (zh) * 2010-02-11 2012-12-12 细胞基因公司 芳基甲氧基异吲哚啉衍生物和包括其的组合物及它们的使用方法
CN104837491A (zh) * 2012-08-09 2015-08-12 细胞基因公司 利用3-(4-((4-(吗啉代甲基)苯甲基)氧基)-1-氧代异二氢吲哚-2-基)哌啶-2,6-二酮治疗癌症的方法
CN105566290A (zh) * 2014-10-30 2016-05-11 康朴生物医药技术（上海）有限公司 异吲哚啉衍生物、其中间体、制备方法、药物组合物及应用
CN106551934A (zh) * 2015-09-29 2017-04-05 康朴生物医药技术（上海）有限公司 一种药物组合物及其应用
WO2018108147A1 (fr) * 2016-12-16 2018-06-21 康朴生物医药技术（上海）有限公司 Composition, son application et procédé de traitement
CN112839658A (zh) * 2018-10-01 2021-05-25 细胞基因公司 用于治疗癌症的组合疗法
WO2022007659A1 (fr) * 2020-07-06 2022-01-13 北京诺诚健华医药科技有限公司 Immunomodulateur hétérocyclique

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