JPWO2020123836A5

JPWO2020123836A5 -

Info

Publication number: JPWO2020123836A5
Application number: JP2021533540A
Authority: JP
Publication date: 2022-12-19

Claims

The formula below:

A splicing regulator that is a compound represented by or a pharmaceutically acceptable salt thereof [wherein:
Y is selected from O, S, ^NR6 , and ^CR6R7 ^;
R ¹ , R ² and R ³ are each independently hydrogen, hydroxyl, —O—(C ₁ -C ₆ alkyl) group, —O—C(=O)-(C ₁ -C ₆ alkyl) group , —C(=O)—O—(C ₁ -C ₆ alkyl) groups, and C ₁ -C ₆ alkyl groups;
R ⁴ is a C ₁ -C ₆ alkyl group, -C(=O)-(C ₁ -C ₆ alkyl) group, -C(=O)-(C ₃ -C ₈ carbocyclyl) group, -C(= O)-(C3 _- C8 heterocyclyl) group, and -C ₍ =O) ^-NR6R7 ^;
R ⁵ is hydrogen, hydroxyl, —CH ₂ —OH, —CO ₂ H, —C(=O)—O—(C ₁ -C ₆ alkyl) group, —C(=O)—NR ⁶ R ⁷ , -NR ⁶ -C(=O)-R ⁸ , -OC(=O)-NR ⁶ R ⁷ , -NR ⁶ -C(=O)-R ⁸ , and -NR ⁶ -C(=O) - NR ⁶ R ⁷ ;
R ⁶ and R ⁷ are each independently selected from hydrogen, -R ⁸ , -C(=O)-R ⁸ , and -C(=O)-OR ⁸ ; and R ⁸ is C ₁ _-C6 alkyl groups, C3 _- C8 carbocyclyl groups _, and C3 _- _C8 heterocyclyl groups;
wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently halogen, hydroxyl, C ₁ -C ₆ alkyl, —O—(C ₁ _-C6 alkyl) group, _-CO2H , -C(=O)-(C1 _- C6 alkyl) group, -C ₍ =O)-(C3 _- C8 carbocyclyl) group, -C ₍ = O)—(C ₃ -C ₈ heterocyclyl) group, —NR ⁶ R ⁷ , C ₃ -C ₈ carbocyclyl group, C ₁ -C ₆ alkylhydroxy group, C ₁ -C ₆ alkylalkoxy group, benzyl group, and C ₃ _- C8 heterocyclyl groups, _each of which is represented by halogen, hydroxyl, C1-C3 alkyl groups, C1 _- C3 alkoxy groups, C1 _- C3 haloalkyl groups _, -NH _- _C ₍ =O) (C1 -C ₃ alkyl), and -NH-C(=O)-O-(C ₁ -C ₃ alkyl) optionally substituted independently with 0 or 1 groups selected from substituted with 0 to 3 groups that are

The compound has the formula:

A compound represented by or a pharmaceutically acceptable salt thereof [wherein:
R ⁹ is selected from C ₃ -C ₈ heterocyclyl groups; and R ¹⁰ is selected from hydrogen atoms and C ₁ -C ₆ alkyl groups,
wherein R ⁹ and R ¹⁰ are each independently halogen, hydroxyl, C ₁ -C ₃ alkyl group, C ₁ -C ₃ alkoxy group, —NH ₂ , —NH—(C ₁ -C ₃ alkyl), and -N-(C ₁ -C ₃ alkyl) ₂ substituted with 0 to 3 groups independently selected from].

The compound has the formula:

A compound represented by or a pharmaceutically acceptable salt thereof [wherein:
R ¹¹ is

wherein ^* represents the point of attachment of R ¹¹ to the remainder of the compound;
R ¹² and R ¹³ are each independently selected from a hydrogen atom and methyl] ,
Said compound is

and pharmaceutically acceptable salts thereof .

the compound is

and pharmaceutically acceptable salts thereof, wherein the compound comprises

or a pharmaceutically acceptable salt thereof.

A compound comprising a linker-payload of formula LH or a pharmaceutically acceptable salt thereof, wherein L is a linker and H is splicing modulation according to any one of claims 1-4. is a drug, H is covalently attached to L via any atom, where the valence of the atom covalently attached to L is not exceeded, and L is a cleavable linker; compound or a pharmaceutically acceptable salt thereof.

The formula below:

A compound selected from: wherein L is a linker, the linker may be a cleavable linker, or a pharmaceutically acceptable salt thereof.

the linker is a cleavable linker comprising at least one cleavable moiety, and the linker is
(i) a cleavable peptide moiety, which may comprise valine-citrulline (Val-Cit) or valine-alanine (Val-Ala); or
(ii) a cleavable glucuronide moiety, wherein said cleavable glucuronide moiety may be cleavable by an enzyme, said cleavable glucuronide moiety may be cleavable by a glucuronidase, said cleavable glucuronide moiety; may be cleavable by β-glucuronidase, a cleavable glucuronide moiety
7. A compound according to claim 5 or 6, comprising

8. The compound of claim 7, wherein the linker comprises a maleimide (Mal) moiety, said maleimide moiety may comprise maleimidocaproyl (MC), and the linker may comprise MC-Val-Cit or MC-Val-Ala. .

said linker comprises at least one Spacer unit,
(i) said Spacer unit comprises a polyethylene glycol (PEG) moiety, wherein said PEG moiety is -(PEG) _ｍm -, where m is an integer from 1 to 10 and m is 2; or
(ii) said Spacer unit comprises an alkyl moiety, wherein said alkyl moiety is —(CH _２2 ) _ｎn -, where n is an integer from 1 to 10, n is 2, 5 or 6;
and said spacer unit may be attached to a maleimide (Mal) moiety (“Mal-spacer unit”).

Either the cleavable portion of the linker is directly tethered to the splicing modulating agent, or a spacer unit connects the cleavable portion of the linker to the splicing modulating agent, and cleavage of the cleavable portion releases the splicing modulating agent from the linker. A compound according to any one of claims 7 to 9, optionally wherein the Spacer unit connecting the cleavable portion of the linker to the splicing regulator may be self-immolative.

The spacer unit that links the cleavable portion of the linker to the splicing modulator comprises p-aminobenzyl (pAB) or p-aminobenzyloxycarbonyl (pABC), pAB or pABC linking the cleavable portion of the linker to the splicing modulator. and the cleavable portion of the linker may comprise a cleavable peptide portion or amino acid unit comprising Val-Cit or Val-Ala, the linker being Val-Cit-pAB, Val-Ala-pAB, Val-Cit- pAB or Val-Ala-pABC, the linker may comprise MC-Val-Cit-pAB, MC-Val-Ala-pAB, MC-Val-Cit-pAB or MC-Val-Ala-pABC; 11. A compound according to claim 10.

Formula (I):
Ab-(LH) _p (I)
[In the formula:
Abs are antibodies or antigen-binding fragments that target neoplastic cells;
H is a splicing regulator;
L is a linker that covalently links the Ab to H; and p is an integer from 1 to 15]
of antibody-drug conjugates.

wherein the antibody or antigen-binding fragment is
(i) neoplastic cells derived from hematologic malignancies which may be selected from B-cell malignancies, leukemia, lymphoma, myeloma, acute myelogenous leukemia and multiple myeloma; or
(ii) may be selected from breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct cancer, melanoma, colon cancer, cervical cancer, pancreatic cancer, renal cancer, colorectal cancer, and esophageal cancer Neoplastic cells derived from solid tumors
13. The antibody-drug conjugate of claim 12, which targets

wherein the antibody or antigen-binding fragment is
(i) targeting HER2-expressing cells;
wherein said antibody or antigen-binding fragment is an anti-HER2 antibody or antigen-binding fragment;
three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein said antibody or antigen-binding fragment comprises the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2), and SEQ ID NO:6 (LCDR3); and / or
The antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20.
well here
said antibody or antigen-binding fragment comprises a human IgG1 heavy chain constant region; and/or
said antibody or antigen-binding fragment comprises a human Ig kappa light chain constant region
also good;
(ii) targeting CD138-expressing cells;
wherein said antibody or antigen-binding fragment is an anti-CD138 antibody or antigen-binding fragment;
three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein said antibody or antigen-binding fragment comprises the amino acid sequences of SEQ ID NO: 7 (HCDR1), SEQ ID NO: 8 (HCDR2), and SEQ ID NO: 9 (HCDR3); three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 10 (LCDR1), SEQ ID NO: 11 (LCDR2), and SEQ ID NO: 12 (LCDR3); and / or
The antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:21 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:22
well here
said antibody or antigen-binding fragment comprises a human IgG2a heavy chain constant region; and/or
said antibody or antigen-binding fragment comprises a human Ig kappa light chain constant region
or
(iii) targeting EPHA2-expressing cells;
wherein the antibody or antigen-binding fragment is an anti-EPHA2 antibody or antigen-binding fragment;
three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein said antibody or antigen-binding fragment comprises the amino acid sequences of SEQ ID NO: 13 (HCDR1), SEQ ID NO: 14 (HCDR2), and SEQ ID NO: 15 (HCDR3); and; three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 16 (LCDR1), SEQ ID NO: 17 (LCDR2), and SEQ ID NO: 18 (LCDR3); / or
The antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:23 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:24.
well here
said antibody or antigen-binding fragment comprises a human IgG1 heavy chain constant region; and/or
said antibody or antigen-binding fragment comprises a human Ig kappa light chain constant region
14. The antibody-drug conjugate of claim 12 or 13, which may be

(i) a splicing regulator of any one of claims 1-4, or a pharmaceutically acceptable salt thereof; (ii) a compound of any one of claims 5-11, or (iii) ) A pharmaceutical composition comprising the antibody-drug conjugate of any one of claims 12-14 and a pharmaceutically acceptable carrier.

A splicing modulator according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, according to any one of claims 5 to 11, for use in the treatment of neoplastic disorders. or the antibody-drug conjugate of any one of claims 12-14.

A splicing modulator according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, any one of claims 5 to 11, for use in the manufacture of a medicament for the treatment of neoplastic disorders A compound according to one claim or an antibody-drug conjugate according to any one of claims 12-14.

wherein the neoplastic disorder is
(i) HER2-expressing breast cancer, ovarian cancer, gastric cancer, lung cancer, uterine cancer, osteosarcoma, or salivary duct cancer, wherein said lung cancer is lung adenocarcinoma and/or said uterine cancer is serous endometrium may be cancer;
(ii) multiple myeloma expressing CD138; or
(iii) breast cancer, prostate cancer, ovarian cancer, lung cancer, melanoma, colon cancer, or esophageal cancer that expresses EPHA2;
A splicing modulator, compound or antibody-drug conjugate for use according to claim 16 or 17.

Any of claims 16-18 for use in the treatment of neoplastic disorders in combination with checkpoint inhibitors targeting CTLA4, PD1, PDL1, OX40, CD40, GITR, LAG3, TIM3 and/or KIR A splicing modulator, compound or antibody-drug conjugate for use according to claim 1.

A neo-antigen vaccine comprising at least one neo-antigen peptide or at least one neo-antigen mRNA, wherein said at least one neo-antigen peptide or at least one neo-antigen mRNA is in an effective amount. The splicing modulator of claim 1 or a pharmaceutically acceptable salt thereof, the compound of any one of claims 5-11 or the antibody-drug conjugate of any one of claims 12-14. A neo-antigen vaccine comprising a neo-antigen sequence induced by contacting the gate with a neoplastic cell.