阅读说明：本技术 Pim激酶抑制剂组合物，方法和其用途 (PIM kinase inhibitor compositions, methods and uses thereof ) 是由 马克·J·布尔克 布兰登·陈 李静怡 肖恩·巴克罕 于 2018-11-05 设计创作，主要内容包括：本申请涉及用作PIM激酶抑制剂的式(I)和(II)化合物及其组合物。还提供了在治疗患有癌性恶性肿瘤的个体中使用PIM抑制剂的合成方法和方法。(The present application relates to compounds of formula (I) and (II) and compositions thereof, useful as PIM kinase inhibitors. Also provided are synthetic methods and methods of using PIM inhibitors in the treatment of individuals having cancerous malignancies.)

1. A compound of formula (I) or (II),

formula (I)

Formula (II)

Or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, prodrug, or isotopic variant thereof, wherein:

each A, B, C and D is the same or different and is independently selected from H, halogen, -N₃，-CN，-NO₂，-OH，-OCF₃.-OCH₂F，-OCF₂H，-CF₃，-SR¹，-S(＝O)R²，-S(＝O)₂R²，-OS(＝O)₂F，-OS(＝O)₂(OR²)，-S(＝O)₂(OR²)，-NR³S(＝O)₂R²，-S(＝O)₂N(R³)₂，-OC(＝O)R²，-CO₂R³，-OR³，-N(R³)₂，-NR³C(＝O)R²，-NR³C(＝O)OR³，-NR³C(＝O)N(R³)₂，CH₂NH₂，-CH₂N(R³)₂，-CH₂SR¹，-C(＝O)NH₂，-C(＝O)N(R³)₂，-C(＝O)R³Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl or a residue selected from, for example, haloalkyl, alkenyl, arylalkyl, alkoxyalkyl, hydroxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, acyloxyalkyl, cyanoalkyl, amidinoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, alkylaryl, aminoalkyl, heteroaryl, carbonylalkyl, aminothioalkyl, nitroguanidinoalkyl, protecting group, glycosylsugar, aminosugar, or alkylsugar residue;

Each A ', B ', C and D ' is the same or different and is independently selected from H, halogen, -N₃，-CN，-NO₂，-OH，-OCF₃.-OCH₂F，-OCF₂H，-CF₃，-SR¹，-S(＝O)R²，-S(＝O)₂R²，-OS(＝O)₂F，-OS(＝O)₂(OR²)，-S(＝O)₂(OR²)，-NR³S(＝O)₂R²，-S(＝O)₂N(R³)₂，-OC(＝O)R²，-CO₂R³，-N(R³)₂，-OR³，-NR³C(＝O)R²，-NR³C(＝O)OR³，-NR³C(＝O)N(R³)₂，CH₂NH₂，-CH₂N(R³)₂，-CH₂SR¹，-C(＝O)NH₂)-C(＝O)N(R³)₂，-C(＝O)R³Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or an optional substituent selected from, for example, haloalkyl, alkenyl, arylalkyl, alkoxyalkyl, hydroxyalkyl, monoalkylarylalkyl, dialkylaminoalkyl, acylaminoalkyl, acyloxyalkyl, cyanoalkyl, amidinoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, alkylaryl, aminoalkyl, heteroaryl, carbonylalkyl, aminothioalkyl, nitroguanidinoalkyl, a protecting group, a glycosyl, an arylsugar or an alkylsaccharide residue;

each E, F, G and M is independently C or N;

each E ', F', G 'and M' is independently C or N;

y and Z are each independently H, -OH, -OR³，N(R³)₂Halogen, -N₃Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or Y and Z may be combined to represent O, N (NR)³) N (OH) or S corresponds to C ═ O, C ═ NNR³C ═ NOH, or C ═ S group;

R¹is H or a linear or branched substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R²is a linear or branched substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each R³Independently H, linear or branched substituted or unsubstituted alkyl. Substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted acyl (-C (═ O) R¹) Or two R³Together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring;

each Q and R is independently H, -S (═ O) R²，-S(＝O)₂R²，-NR³S(＝O)₂R²，-S(＝O)₂N(R³)₂，-C(＝O)R²，-CO₂R³，-N(R³)₂，-C(O)N(R³)₂A linear or branched substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group, a natural or non-natural substituted or unsubstituted saccharide, a natural or non-natural substituted or unsubstituted glycosylsaccharide,

A natural or non-natural substituted or unsubstituted glycosylalkylglycosyl, a natural or non-natural substituted or unsubstituted saccharide, an aminosugar, or an alkylsaccharide, wherein Q and R are linked, a substituted or unsubstituted alkyl, wherein Q and R are linked, a substituted or unsubstituted cycloalkyl, wherein Q and R are linked, a substituted or unsubstituted heterocycloalkyl, wherein Q and R are linked, a substituted or unsubstituted aryl, wherein Q and R are linked, or a substituted or unsubstituted heteroaryl, wherein Q and R are linked to form a ring;

each of U, V, U' and V is independently H, OH, OR³，N(R³)₂Halogen, -N₃Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or U and V and/or U' and V may be combined to represent O, N (NR)³) N (OH) or corresponding to C ═ O, C ═ NNR³C ═ NOH, or C ═ S of S;

each X is H, -OH, -OR³，N(R³)₂Halogen, -N₃，-NO₂Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, prodrug, or isotopic variant thereof, wherein Y and Z are H.

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, prodrug, or isotopic variant thereof, wherein Y and Z together form a carbon-oxygen double bond (C ═ 0).

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate, hydrate thereof,n-oxides, prodrugs or isotopic variations, wherein X is-CH₂N(CH₃)₂And U, V, U ', and V is H, and wherein at least one of a, B, C, D, a', B ', C', D 'is not hydrogen or at least one of E, F, G, M, E', G ', F', M is not carbon.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, prodrug or isotopic variant thereof, wherein Q and/or R is an alkyl or aralkyl chain containing at least one heteroatom.

6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, prodrug or isotopic variant thereof, wherein Q and/or R is a branched or straight chain, substituted or unsubstituted carbon chain of 2-6 carbons, connected at a terminal carbon to a heterocycle containing one or more N, S and/or O.

7. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, prodrug or isotopic variant thereof, wherein Q and/or R is a branched or straight chain, substituted or unsubstituted carbon chain of 2 to 6 carbons, connected at a terminal carbon to the N of a heterocycle containing one or more N.

8. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, prodrug or isotopic variation thereof, wherein Q and/or R is a branched or straight chain, substituted or unsubstituted carbon chain of 2-6 carbons joined at a terminal carbon to a piperazinyl or pyrrolidinyl group, a piperazinyl or morpholinyl or imidazolyl or pyrazolyl group.

9. A compound selected from figures 1a-1S or a pharmaceutically acceptable salt, solvate, hydrate or N-oxide, prodrug or isotopic variant thereof.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, prodrug, stereoisomer, enantiomer, enantiomeric mixture, diastereomeric mixture, isotopic variant and metabolite thereof, in combination with a pharmaceutically acceptable excipient, carrier or binder.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, prodrug, or isotopic variant thereof, wherein the compound inhibits the catalytic activity of serine/threonine kinase PIM1, PIM2, and/or PIM 3.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, prodrug, or isotopic variant thereof, wherein the compound selectively inhibits the catalytic activity of one or more PIM kinases.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, prodrug, or isotopic variant thereof, wherein the compound selectively inhibits the catalytic activity of PIM3 kinase.

14. The present invention relates to a method of inhibiting or partially inhibiting PIM kinase activity comprising contacting a PIM kinase with a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, solvate, hydrate or N-oxide, prodrug or isotopic variant thereof.

15. A method according to one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, hydrate or N-oxide, prodrug or isotopic variant thereof, for selectively inhibiting the activity of one or more PIM kinases, said method comprising contacting said PIM kinases with a compound.

16. The method of any one of claims 14-15, wherein the PIM kinase is contacted with the compound in vitro.

17. The method of any one of claims 14-15, wherein the PIM kinase is contacted with the compound in vivo.

18. The method of any one of claims 14-17, wherein the contacting results in substantially complete inhibition of PIM kinase.

19. The method of any one of claims 14-17, wherein said contacting results in partial inhibition of PIM kinase.

20. The method of any one of claims 14-19, wherein contacting modulates cancer cell growth and survival.

21. A method of inhibiting or partially inhibiting PIM kinase activity by a factor of 1.5, 10, 100, 1000 or more selective to PIM1 and PIM2, comprising contacting the three kinases in vitro or in vivo, separately or together, by a method of inhibiting PIM 3.

22. A method for the synthesis of a compound of formula (I), wherein tryptophan or a tryptophan derivative is contacted in vitro with a cell-free extract and/or a combination of enzymes comprising VioA (SEQ ID NO: 1) and VioB (SEQ ID NO: 2) comprising StaP (SEQ ID NO: 5) and StaC (SEQ ID NO: 6) of the cystine pathway, or RebP (SEQ ID NO: 4), RebC (SEQ ID NO: 3) of the rebeck pathway, or homologues of these enzymes, each representing 25% sequence identity or relative to the individual SEQ ID NOs: 1-6 higher, and wherein Y and Z of formula (I) are both H or together form a carbon-oxygen double bond (C ═ O), and wherein Q and R are both H.

23. A method of synthesizing a compound of formula (ii), wherein tryptophan or a tryptophan derivative is contacted in vitro with a cell-free extract and/or a combination of enzymes comprising VioA (SEQ ID NO: 1) and viob (SEQ ID NO: 2) comprising, relative to an individual SEQ ID NO: 1, 2 and 7 or greater, and the compound of formula (iiia) formed thereby is subsequently chemically reacted to introduce the macrocyclic alkyl group of formula (IV) to give the compound of formula (II).

24. A method of treating a patient or subject suffering from a malignant disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, prodrug or isotopic variant thereof.

25. The method of claim 24, wherein the malignant disease is a cancer of the endothelial organs including but not limited to the caecum, pancreas, liver, stomach, intestine, colon, prostate, thyroid, esophagus, lung and gall bladder.

26. The method of claim 25, wherein the cancer is pancreatic cancer, liver cancer, gastric cancer, colorectal cancer, prostate cancer, esophageal adenocarcinoma, squamous cell carcinoma, nasopharyngeal cancer, gastric cancer adenocarcinoma, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, gallbladder adenocarcinoma, prostate adenocarcinoma, colorectal adenocarcinoma, gastrointestinal stromal tumor (GIST), or gastrointestinal cancer tumor.