Gemcitabine monophosphate small molecule drug conjugate

Abstract

This invention provides novel small molecule drug conjugates (SMDCs) for use in the treatment or prevention of cancer and other proliferative conditions characterized by cells expressing cytochrome P4501B1 (CYP1B1) and its allele variants. Furthermore, it provides pharmaceutical compositions comprising one or more such compounds for use in medical therapies, for example, in the treatment or prevention of cancer or other proliferative conditions, and methods for treating cancer or other conditions in human or non-human animal patients. [Solution] Provide a compound of formula (I). TIFF2026102855000243.tif50128

Claims

1. Compound of formula (I): or its pharmaceutically acceptable salts, esters, solvates, or stereoisomers: During the ceremony, -L- is -(C 1 ~C 5 ) Alkylene-OC(O)-,-(C 3 ~C 5 ) Alkenylene-O-, Defined as, A is -(C 1 ~C 5 ) is alkylene-OC(O)-; E is -O-, -OC(O)N(H)-, -OC(S)N(H)-, or -S-, or -SC(O)N(H)-; D is -(C 1 ~C 5 ) alkylene- or -(C 3 ~C 5 ) alkenylene-; Y 1 C=C, carbon or nitrogen, Y 1 If it is nitrogen, then Z 1 It does not exist; Y 4 and Y 5 Each of them is independently either carbon or nitrogen, Y 3 If it is nitrogen, then Z 3 Y does not exist. 4 If it is nitrogen, then Z 5 It does not exist; Y 2 is C or N; Y 5 is an oxygen, carbon, nitrogen, or sulfur atom, Y 5 If it is an oxygen or sulfur atom, then Z 6 It does not exist; Z 1 and Z 2 Each of these, if present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, alkylthiooxy, alkenylthiooxy, alkynylthiooxy, arylthiooxy, aralkylthiooxy, amino, hydroxy, thio, halo, carboxy, formyl, nitro, and cyano, and each alkyl, alkenyl, alkynyl, alkoxy, and aryl moiety may independently be substituted with 1 to 3 halos; Z 3 , Z 4 , and Z 5 Hydrogen, alkyl, deuterated alkyl, C 1～6 Alkoxy, deuterated C 1～6 Each alkyl, alkenyl, alkynyl, aryl, aralkyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, alkylthiooxy, alkenylthiooxy, alkynylthiooxy, arylthiooxy, aralkylthiooxy, amino, hydroxy, thio, halo, carboxy, formyl, nitro, and cyano moieties are independently selected, and each alkyl, alkenyl, alkynyl, alkoxy, and aryl moiety may be independently substituted with 1 to 3 halos; Z 1 , Z 2 , or Z 4 Provided that at least one of them is H; Z 6 The elements are selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, and aralkyl, and each alkyl, alkenyl, alkynyl, alkoxy, and aryl moiety may be independently substituted with 1 to 3 halos; each Z 8 These are independently hydrogen and unsubstituted C 1 ~C 6 Alkyl, substituted C 1 ~C 6 Alkyl, unsubstituted C 1 ~C 6 Alkoxy, unsubstituted deuterated C 1 ~C 6 alkoxy, substituted C 1 ~C 6 Alkoxy and substituted deuterated C 1 ~C 6 The alkoxy is an alkoxy, and the substituted alkyl, alkoxy, and deuterated alkoxy are amino, monosubstituted or disubstituted amino, and cyclic C 1 ~C 5 Alkylamino, imidazolyl, C 1 ~C 6 The molecules are substituted with one or more groups selected from alkylpiperazinyl, morpholino, thiol, thioether, tetrazole, carboxylic acid, ester, amide, monosubstituted or disubstituted amide, N-bonded amide, N-bonded sulfonamide, sulfoxy, sulfonate, sulfonyl, sulfoxy, sulfinate, sphinyl, phosphonooxy, phosphate, or sulfonamide, and each alkyl, alkenyl, alkynyl, alkoxy, and aryl may be substituted with 1 to 3 halos.

2. Y 3 and Y 4 The compound according to claim 1, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof, wherein each of the atoms is carbon.

3. Z 3 , Z 4 and Z 5 These are Halo and Unsubstituted C, respectively. 1 ~C 3 Alkyl, substituted C 1 ~C 3 Alkyl, unsubstituted C 1 ~C 3 alkoxy, substituted C 1 ~C 3 Alkoxy, unsubstituted deuterated C 1 ~C 3 Alkoxy or substituted C 1 ~C 3 A compound according to any one of the above claims, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof, selected from alkoxys, wherein each alkyl and alkoxy moiety can be independently substituted with 1 to 3 halos.

4. Z 3 , Z 4 , and Z 5 Each of the above is selected from bromo, chloro, fluoro, methyl, deuterated methyl which may be substituted with 1 to 3 halos, methoxy which may be substituted with 1 to 3 halos, or deuterated methoxy, and is a compound according to any one of the above claims, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof.

5. Equation (Ia): A compound according to any one of the above claims, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof: During the ceremony, L, Y 1 , Y 2 , Y 5 , Z 3 , Z 4 , Z 5 , and Z 6 Each of these is defined in any one of claims 1 to 4, The effector is the part that is (i) a phosphate derivative of gemcitabine, or (ii) a salt form of a phosphate derivative of gemcitabine.

6. Formulas (Ib-i), (Ib-ii), (Ib-iii), (Ib-iv), (Ib-v), (Ib-vi), (Ib-vii), (Ib-viii), (Ib-ix), (Ib- x), (Ib-xi), (Ib-xii), (Ib-xiii), (Ib-xiv), (Ib-xv), (Ib-xvi), (Ib-xvii), or (Ib-xviii): A compound according to any one of the above claims, having, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer of any of the above formulas: During the ceremony, Z 3 and Z 5 Each of these is independently a halo, a methyl atom which may be substituted with 1 to 3 halos, a methoxy atom which may be substituted with 1 to 3 halos, or a deuterated methoxy atom; Z 4 If present, these are a halo, a methyl atom which may be substituted with 1 to 3 halos, a methoxy atom which may be substituted with 1 to 3 halos, or a deuterated methoxy atom; -L-Effector is -(C 1 ~C 3 ) Alkilen-OC(O)-effector, And: D is -(C 1 ~C 3 ) is alkylene-; E is -O-, -OC(O)N(H)-, -OC(S)N(H)-, -S-, or -SC(O)N(H)-; A is -(C 1 ~C 3 ) is alkylene-OC(O)-; The effector is the part that is (i) a phosphate derivative of gemcitabine, or (ii) a salt form of a phosphate derivative of gemcitabine.

7. The linker region (L) is -C(H) 2 A compound according to any one of the above claims, which is -OC(O)-, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof.

8. Formulas (Id-i), (Id-ii), (Icd-iii), (Id-iv), (Id-v), (Id-vi), (Id-vii), (Id-viii), (Id-ix), (Id-x), (Id-x i), (Id-xii), (Id-xiii), (Id-xiv), (Id-xv), (Id-xvi), (Id-xvii), (Id-xviii), (Id-xix), or (Id-xx): A compound according to claim 1, having, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer of any of the above formulas: During the ceremony, Z 3 、Z 4 、and Z 5 is, independently of one another, methyl which may be substituted by 1 to 3 halos, halo, methoxy which may be substituted by 1 to 3 halos, or deuterated methoxy; M 2 is -O - Na+, -O - Et 3 NH + , -O - K + , -O - NH 4 + is as follows.

9. Z 3 , Z 5 , and Z 4 The compound according to any one of the above claims, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof, wherein, if present, each is a methoxy or deuterated methoxy which may be substituted with 1 to 3 halos.

10. Z 3 and Z 5 However, each is independently bromo or fluoro, and Z 4 The compound according to any one of the above claims, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof, which, if present, is a methoxy or deuterated methoxy which may be substituted with 1 to 3 halos.

11. The compound according to any one of the above claims, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof, wherein the compound is in the form of sodium phosphate or triethylammonium phosphate.

12. The following structure: A compound according to claim 1 having one of the following, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer of any one of compounds 1 to 9.

13. Equation (Id-ii-1): The compound according to claim 1, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof: During the ceremony, Z 3 , Z 4 , and Z 5 Each of these is independently hydrogen, methyl which may be substituted with 1 to 3 halos, halo, methoxy which may be substituted with 1 to 3 halos, or deuterated methoxy; Each M 2 OH and O - (M 1 (M) is independently selected from the group consisting of 1 Each of these is, independently, a metal cation, an ammonium cation, an alkylammonium cation, or an amino acid cation when it appears.

14. (M 1 ) but, Na + Ca 2+ , K + Mg 2+ Zn 2+ NH 4+ (HNEt3) + Meglumine-H + Tromethamine-H + Diethanolamine-H + Lysine-H + , and arginine-H + A compound according to claim 13, selected from the group consisting of the following.

15. Z 5 and Z 3 The compound according to any one of claims 13 to 14, wherein each of them is independently methoxy.

16. Z 4 The compound according to any one of claims 13 to 15, wherein is hydrogen.

17. The aforementioned compound, The compound according to any one of claims 13 to 16, or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof.

18. A composition comprising a compound according to any one of the above claims together with a pharmaceutically acceptable carrier, or a pharmaceutically acceptable salt, ester, amide, or solvate of a compound according to any one of the above claims together with a pharmaceutically acceptable carrier.

19. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, ester, amide, or solvate, for use in pharmaceuticals.

20. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, ester, amide, or solvate, for use in a method of treating or prophylactic a proliferative condition.

21. The compound, or a pharmaceutically acceptable salt, ester, amide, or solvate, for use in a method of treatment or prevention according to claim 20, wherein the proliferative state is a cancer selected from cancers of the bladder, brain, breast, colon, head and neck, kidney, lung, liver, ovary, pancreas, prostate, or skin.

22. Use of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, ester, amide, or solvate, for the preparation of a medical agent for use in a method of treating or prophylactic conditions.

23. A method for diagnosing a patient for the presence of tumor cells expressing the CYP1B1 enzyme, (a) A step of administering a specific compound according to any one of claims 1 to 21 to the patient, (b) A step of determining the amount of the corresponding hydroxylated metabolite that is subsequently produced; and (c) A step of correlating the amount with the presence or absence of tumor cells in the patient. Methods that include...

24. (1) Identify the presence of a tumor in the patient; (2) To treat a patient identified as being in need of the treatment by administering a therapeutically or prophylactically useful amount of the compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, ester, amide, or solvate thereof. method.

25. A step of administering a therapeutically useful amount of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, ester, amide, or solvate thereof, to a subject in need thereof. A method for treating proliferative conditions, including [specific condition].

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