CAK inhibitors and uses thereof

A method of inhibiting CAK enzyme, comprising the step of contacting said CAK with a compound of formula I′:

• 30
• wherein:
• X is N or ═C;
• Y is ═C when X is N;
• Y is N when X is ═C;
• ring A, taken together with X, is a 5-7 membered monocyclic or bicyclic carbocyclic or heterocyclic aromatic or non-aromatic ring;
• wherein ring A has up to 3 substituents independently selected from halogen, —OH, —NO2, —CF3, —OCF3, R, —OR, —O-benzyl, —O-phenyl, 1,2-methylenedioxy, —NR2, —COR, —CO2R, —CON(R)2, —NRCON(R)2, —NRCOR, —NRCO2R, —CO—COR, —CONRN(R)2, —SO2R, —SOR, —SON(R)2, —SO2N(R)2 and —NRSO2R;
• wherein each R is independently H, (C1-C6) straight or branched alkyl, (C2-C6) straight or branched alkenyl or alkynyl;
• one of Z1 and Z3 is selected from —CN, —N3, acetenyl or cyclopropyl, and the other of Z1 and Z3 is:
• 31
• wherein:
• n is 0 or 1;
• W is O or S;
• V is —NH—;
• Ar is a 5-10 membered monocyclic or bicyclic aromatic carbocyclic or aromatic heterocyclic ring;
• wherein Ar has up to 3 substituents selected from halogen, —OH, —NO2, —CF3, —OCF3, R, —OR, —O-benzyl, —O-phenyl, 1,2-methylenedioxy, —NR2, —COR, —CO2R, —CON(R)2, —NRCON(R)2, —NRCOR, —NRCO2R, —CO—COR, —CONRN(R)2, —SO2R, —SOR, —SON(R)2, —SO2N(R)2 and —NRSO2R;
• wherein each R is independently as defined above;
• Z2 is NHR1;
• wherein R1 is H or C1-C6 straight or branched alkyl;
• provided that when X is N, Y is ═C, Z is CN, Z is —NH2. W is O, and ring A, together with X is selected from:
• 32
• then, n is 0, and Ar is not unsubstituted phenyl.

A compound having the formula (I′):

• 35
• wherein:
• X is N or ═C;
• Y is ═C when X is N;
• Y is N when X is ═C;
• ring A, taken together with X, is a 5-7 membered monocyclic or bicyclic carbocyclic or heterocyclic aromatic or non-aromatic ring;
• wherein ring A has up to 3 substituents independently selected from halogen, —OH, —NO2, —CF3, —OCF3, R, —OR, —O-benzyl, —O-phenyl, 1,2-methylenedioxy, —NR2, —COR, —CO2R, —CON(R)2, —NRCON(R)2, —NRCOR, —NRCO2R, —CO—COR, —CONRN(R)2, —SO2R, —SOR, —SON(R)2, —SO2N(R)2 and —NRSO2R;
• wherein each R is independently H, (C1-C6) straight or branched alkyl, (C2-C6) straight or branched alkenyl or alkynyl;
• one of Z1 and Z3 is selected from —CN, —N31 acetenyl or cyclopropyl, and the other of Z1 and Z3 is:
• 36
• wherein:
• n is 0 or 1;
• W is O or S;
• V is —NH—;
• Ar is a 5-10 membered monocyclic or bicyclic aromatic carbocyclic or aromatic heterocyclic ring;
• wherein Ar has up to 3 substituents selected from halogen, —OH, —NO2, —CF3, —OCF3, R, —OR, —O-benzyl, —O-phenyl, 1,2-methylenedioxy, —NR2, —COR, —CO2R, —CON(R)2, —NRCON(R)2, —NRCOR, —NRCO2R, —CO—COR, —CONRN(R)2, —SO2R, —SOR, —SON(R)2, —SO2N(R)2 and —NRSO2R;
• wherein each R is independently as defined above;
• Z2 is NHR1;
• wherein R1 is H or C1-C6 straight or branched alkyl;
• provided that when X is N, Y is ═C, Z1 is CN, Z2 is —NH2, W is O, and ring A, together with X is selected from:
• 37
• then, n is 0, and Ar is not unsubstituted phenyl.