Pyrimido-diazepinone kinase scaffold compounds and methods of treating dclk1/2-mediated disorders

A method of treating a disease in a subject wherein the disease is mediated by a kinase that is doublecortin-like kinase (DCLK1/2), or a method for reducing DCLK1/2-dependent cell growth, or a method of inhibiting DCLK1/2 in a subject identified as in need of such treatment, the method comprising administering to the subject a compound of formula A-1:

• or a pharmaceutically acceptable salt, ester or prodrug thereof,
• wherein,
• X is CHR4, CR4, NH, NR4 or N;
• Y is NR5, N, S, SO, SO2, O, CHR5, or CR5;
• wherein at least one of X and Y is NH, NR4, NR5, N, S, SO, SO2, or O;
• A is a single bond or double bond;
• B is a single bond or double bond, wherein both A and B are not double bonds;
• R′ is H or alkyl;
• L is absent, S, SO, SO2, or CO;
• R1 is H, alkyl, alkenyl, alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
• or R1 is aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic;
• wherein R1 may be optionally substituted;
• R2 is hydrogen or optionally substituted alkyl;
• R3 is hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted;
• R4 is hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted;
• R5 is hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted;
• or R3 and X, together with the atoms to which they are attached, form a 3-8 membered carbocyclic, aryl, heterocyclic, or heteroaryl;
• each of which is optionally substituted;
• or X and Y, together with the atoms to which they are attached, form a 3-8 membered carbocyclic, aryl, heterocyclic, or heteroaryl;
• each of which is optionally substituted;
• and
• R6 is hydrogen or optionally substituted alkyl.

A method of treating a disease in a subject wherein the disease is mediated by doublecortin-like kinase (DCLK1) and/or doublecortin-like kinase 2 (DCLK2), or a method of inhibiting DCLK1/2 in a subject identified as in need of such treatment, or a method of reducing DCLK1/2-dependent cell growth, the method comprising administering to the subject a compound selected from the group consisting of:

• formula I-2:
• or a pharmaceutically acceptable salt, ester or prodrug thereof,
• wherein,
• A is a single bond or double bond;
• R′ is H or alkyl;
• L is absent, S, SO, SO2, or CO;
• X is an optional substituent;
• R1 is H, alkyl, alkenyl, alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
• or R1 is aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic;
• wherein R1 may be optionally substituted;
• R2 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;
• and
• R6 is hydrogen or optionally substituted alkyl,
• formula II-2:
• or a pharmaceutically acceptable salt, ester or prodrug thereof,
• wherein,
• R′ is H or alkyl;
• L is absent, S, SO, SO2, or CO;
• X is an optional substituent as defined for formula I;
• E is NR2 or CHR2;
• R1 is H, alkyl, alkenyl, alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
• or R1 is aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic;
• wherein R1 may be optionally substituted;
• R2 is, independently for each occurrence, hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;
• and
• R6 is hydrogen or optionally substituted alkyl,
• formula III-2:
• or a pharmaceutically acceptable salt, ester or prodrug thereof,
• wherein,
• R′ is H or alkyl;
• L is absent, S, SO, SO2, or CO;
• X is an optional substituent as defined for formula I;
• R1 is H, alkyl, alkenyl, alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
• or R1 is aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic;
• wherein R1 may be optionally substituted;
• R2 is, independently for each occurrence, hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;
• and
• R6 is hydrogen or optionally substituted alkyl,
• formula IV-2:
• or a pharmaceutically acceptable salt, ester or prodrug thereof,
• wherein,
• R′ is H or alkyl;
• L is absent, S, SO, SO2, or CO;
• X is an optional substituent as defined for formula I;
• R1 is H, alkyl, alkenyl, alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
• or R1 is aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic;
• wherein R1 may be optionally substituted;
• R2 is, independently for each occurrence, hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;
• and
• R6 is hydrogen or optionally substituted alkyl,
• formula V-2:
• or a pharmaceutically acceptable salt, ester or prodrug thereof,
• wherein,
• X is an optional substituent as defined for formula I;
• R2 is hydrogen or optionally substituted alkyl;
• R3 is —OH or —O-(optionally substituted alkyl);
• R4 is hydrogen or optionally substituted alkyl;
• and
• R6 is hydrogen or optionally substituted alkyl, or
• formula VI-2:
• or a pharmaceutically acceptable salt, ester or prodrug thereof,
• wherein,
• R′ is H or alkyl;
• L is absent, S, SO, SO2, or CO;
• X is an optional substituent as defined for formula I;
• R1 is H, alkyl, alkenyl, alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
• or R1 is aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic;
• wherein R1 may be optionally substituted;
• R2 is, independently for each occurrence, hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;
• or
• two X moieties on adjacent atoms of the thiophene ring can form, together with the atoms to which they are attached, a phenyl ring;
• and
• R6 is hydrogen or optionally substituted alkyl,
• formula VII-2:
• or a pharmaceutically acceptable salt, ester or prodrug thereof,
• wherein,
• R′ is H or alkyl;
• L is absent, S, SO, SO2, or CO;
• X is an optional substituent as defined for formula I;
• R1 is H, alkyl, alkenyl, alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
• or R1 is aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic;
• wherein R1 may be optionally substituted;
• R2 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;
• and
• R6 is hydrogen or optionally substituted alkyl,
• formula VIII-2:
• or a pharmaceutically acceptable salt, ester or prodrug thereof,
• wherein,
• R′ is H or alkyl;
• L is absent, S, SO, SO2, or CO;
• X is an optional substituent as defined for formula I;
• Z is O or S;
• R1 is H, alkyl, alkenyl, alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
• or R1 is aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic;
• wherein R1 may be optionally substituted;
• R2 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;
• and
• R6 is hydrogen or optionally substituted alkyl, and
• formula IX-2:
• or a pharmaceutically acceptable salt, ester or prodrug thereof,
• wherein,
• A is a single bond or double bond;
• R′ is H or alkyl;
• L is absent, S, SO, SO2, or CO;
• Y is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;
• R1 is H, alkyl, alkenyl, alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
• or R1 is aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic;
• wherein R1 may be optionally substituted;
• R2 and R2′ are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;
• or Y and R2′ can form, together with the atoms to which they are attached, a five-membered ring;
• and
• R6 is hydrogen or optionally substituted alkyl.

A compound of formula F-1:

• or a pharmaceutically acceptable salt, ester or prodrug thereof,
• wherein,
• R1 is alkyl, aryl, heteroaryl, heterocyclic, or carbocyclic, wherein R1 may be optionally substituted;
• R2 is hydrogen or optionally substituted alkyl;
• R5 is hydrogen or methyl, optionally substituted alkyl, optionally substituted aralkyl, or optionally substituted carbocyclic;
• and
• R6 is hydrogen or optionally substituted alkyl;
• each R7 is independently alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, carbocyclic, alkoxy, NH(alkyl), NH(aryl), N(alkyl)(alkyl), or N(alkyl)(aryl), each of which may be optionally substituted;
• halo, nitro, or cyano;
• and
• p is 0-4.