Novel homopiperazine derivatives as protein tyrosine kinase inhibitors and pharmaceutical use thereof

A compound of general formula I

• wherein
• m is 0, 1 or 2;
• n is 2 or 4;
• R1 is selected from the group consisting of hydrogen, halogen, cyano, —NH2, —SO2NH2, —SONH2, and —CONH2;
• or R1 is selected from the group consisting of alkyl-, heteroalkyl-, cycloalkyl-, heterocyclyl-, R1aO—, R1aS—, (R1a)2N—, R1b—C(═O)N(R1c)—, R1bO—C(═O)N(R1c)—, (R1b)2N—C(═O)N(R1c)—, R1b—S(═O)2N(R1c)— and (R1b)2N—S(═O)2N(R1c)— either of which may be optionally substituted with one or more R1d;
• R1a is hydrogen;
• or R1a independently at each occurrence is selected from the group consisting of alkyl-, heteroalkyl-, cycloalkyl-, heterocyclyl- either of which may be optionally substituted with one or more R1e;
• or in the case where two R1as are attached to the same N, they may together with the N atom to which they are attached form a heterocycle which may be optionally substituted with one or more R1e;
• R1b and R1c independently at each occurrence are selected from the group consisting of hydrogen, alkyl-, heteroalkyl-, cycloalkyl-, heterocyclyl- either of which may be optionally substituted with one or more R1e;
• or in the case where two R1bs are attached to the same N, they may together with the N atom to which they are attached form a heterocycle which may be optionally substituted with one or more R1e;
• R1d and R1e independently at each occurrence are selected from the group consisting of halogen, cyano, hydroxy, oxo, —NH2, —SO2NH2, —CONH2, alkyl-, heteroalkyl-, cycloalkyl-, heterocyclyl-, R1fO—, R1fS—, (R1f)2N—, R1f—C(═O)N(R1f)—, (R1f)2N—C(═O)N(R1f)—, (R1f)2N—C(═O)O—, (R1f)2N—S(═O)2—, R1f—S(═O)2N(R1f)—
• R1f independently at each occurrence is selected from the group consisting of hydrogen, alkyl-, heteroalkyl-, cycloalkyl-, heterocyclyl-
• or in the case where two R1fs are attached to the same N, they may together with the N atom to which they are attached form a heterocycle
• R2 is independently at each occurrence a covalent bond or alkyl- or heteroalkyl- group, where any two R2s are attached to the same C ring atom, and together with this C ring atom said two R2s form a carbocycle or heterocycle, hence always forming a spirocyclic homopiperazine.
• R3 independently at each occurrence is selected from the group consisting of halogen, cyano, hydroxy, oxo, alkyl-, heteroalkyl-, cycloalkyl-, heterocyclyl-, R3aO—, R3aS—, (R3a)2N—, R3aC(═O)—, R3aO—C(═O)—, (R3a)2N—C(═O)—, R3a—C(═O)N(R3b)—, R3aO—C(═O)N(R3b)—, R3a—C(═O)O—, (R3a)2N—C(═O)O—, R3a—S(═O)2—, (R3a)2N—S(═O)2—, R3a—S(═O)2N(R3b)—
• R3a and R3b independently at each occurrence are selected from the group consisting of hydrogen, alkyl-, heteroalkyl-, cycloalkyl-, heterocyclyl-
• or in the case where two R1as are attached to the same N, they may together with the N atom to which they are attached form a heterocycle
• R4 is selected from the group consisting of hydrogen or
• wherein
• X is O or S;
• G1 is selected from the group consisting of alkyl-, heteroalkyl-, alkenyl-, alkynyl-, cycloalkyl-, cycloalkenyl-, cycloalkynyl-, heterocyclyl-, cycloalkylalkyl-, heterocyclylalkyl-, RG1aO-L, RG1aS-L-, (RG1a)2N-L-, RG1a—C(═O)-L-, RG1aO—C(═O)-L-, (RG1a)2N—C(═O)-L-, RG1a—C(═O)N(RG1b)-L-, RG1aO—C(═O)N(RG1b)-L-, (RG1a)2N—C(═O)N(RG1b)-L-, RG1a—C(═O)O-L-, (RG1a)2N—C(═O)O-L, RG1a—S(═O)2-L-, (RG1a)2N—S(═O)2-L-, RG1a—S(═O)2N(RG1b)-L, (RG1a)2N—S(═O)2N(RG1b)—, aryl-, aryloxy-, arylalkyl-, arylalkyloxy-, aryloxyalkyl-, aryloxyalkyloxy-, heteroaryl-, heteroaryloxy-, heteroarylalkyl-, heteroarylalkyloxy-, heteroaryloxyalkyl-, heteroaryloxyalkyloxy- either of which may be optionally substituted with one or more RG1c;
• RG1a and RG1b independently at each occurrence are selected from the group consisting of hydrogen, alkyl-, heteroalkyl-, alkenyl-, alkynyl-, cycloalkyl-, heterocyclyl-, aryl- and heteroaryl- either of which may be optionally substituted with one or more RG1c;
• or in the case where two RG1as are attached to the same N, they may together with the N atom to which they are attached form a heterocycle which may be optionally substituted with one or more RG1c;
• RG1c is selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, oxo, —NH2, —SO2NH2, —SONH2, —CONH2
• or RG1c is selected from the group consisting of alkyl-, heteroalkyl-, cycloalkyl-, alkenyl-, alkynyl-, alkenylalkyl-, alkynylalkyl-, cycloalkenyl-, cycloalkylalkyl-, cycloalkylalkenyl-, cycloalkylalkynyl-, cycloalkenylalkyl-, cycloalkenylalkenyl-, cycloalkenylalkynyl-, heterocyclyl-, heterocyclylalkyl-, heterocyclylalkenyl-, heterocyclylalkynyl-, RG1dO-L-, RG1dS-L-, (RG1d)2N-L, RG1d—C(═O)-L, RG1dO—C(═O)-L-, (RG1d)2N—C(═O)-L-, RG1d—C(═O)N(RG1e)-L-, RG1dO—C(═O)N(RG1e)-L-, (RG1d)2N—C(═O)N(RG1e)-L-, RG1d—C(═O)O-L-, (RG1d)2N—C(═O)O-L-, (RG1d)—S(═O)2-L-, (RG1d)2N—S(═O)2-L-, RG1d—S(═O)2N(RG1e)-L-, (RG1d)2N—S(═O)2N(RG1e)-L-, aryl-, arylalkyl-, arylcycloalkyl-, aryloxy-, aryloxyalkyl-, aryloxycycloalkyl-, heteroaryl-, heteroarylalkyl-, heteroarylcycloalkyl, heteroaryloxy-, heteroaryloxyalkyl-, and heteroaryloxycycloalkyl-
• either of which may be optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, oxo, —NH2, —SO2NH2, —SONH2, —CONH2
• RG1d and RG1e independently at each occurrence are selected from the group consisting of hydrogen or of alkyl-, heteroalkyl-, alkenyl-, alkynyl-, cycloalkyl-, heterocyclyl-, cyclolalkylalkyl-, heterocyclylalkyl-, aryl-, arylalkyl-, heteroaryl-, heteroarylalkyl- and alkoxyalkyl-
• either of which may be optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, oxo, —NH2, —SO2NH2, —SONH2, —CONH2
• or in the case where two RG1ds are attached to the same N, they may together with the N atom to which they are attached form a heterocycle which may be optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, oxo, —NH2, —SO2NH2, —SONH2, —CONH2
• G2 is selected from the group consisting of alkyl-, heteroalkyl-, alkenyl-, alkynyl-, cycloalkyl-, cycloalkenyl-, cycloalkynyl-, heterocyclyl-, cycloalkylalkyl-, heterocyclylalkyl-, RG2aO-L-, RG2aS-L-, (RG2a)2N-L-, RG2a—C(═O)-L-, RG2aO—C(═O)-L-, (RG2a)2N—C(═O)-L-, RG2a—C(═O)N(RG2b)-L-, RG2aO—C(═O)N(RG2b)-L-, (RG2a)2N—C(═O)N(RG2b)-L-, RG2a—C(═O)O-L-, (RG2a)2N—C(═O)O-L-, RG2a—S(═O)2-L-, (RG2a)2N—S(═O)2-L-, RG2a—S(═O)2N(RG2b)-L-, (RG2a)2N—S(═O)2N(RG2b)-L-, aryloxy-, arylalkyl-, arylalkyloxy-, aryloxyalkyl-, aryloxyalkyloxy-, heteroaryl-, heteroaryloxy-, heteroarylalkyl-, heteroarylalkyloxy-, heteroaryloxyalkyl-, heteroaryloxyalkyloxy- either of which may be optionally substituted with one or more RG2c;
• RG2a and RG2b independently at each occurrence are selected from the group consisting of hydrogen, alkyl-, heteroalkyl-, alkenyl-, alkynyl-, cycloalkyl-, heterocyclyl-, aryl- and heteroaryl- either of which may be optionally substituted with one or more RG2c;
• or in the case where two RG2as are attached to the same N, they may together with the N atom to which they are attached form a heterocycle which may be optionally substituted with one or more RG2c;
• RG2c is selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, oxo, —NH2, —SO2NH2, —SONH2, —CONH2
• or RG2c is selected from the group consisting of alkyl-, heteroalkyl-, cycloalkyl-, alkenyl-, alkynyl-, alkenylalkyl-, alkynylalkyl-, cycloalkenyl-, cycloalkylalkyl-, cycloalkylalkenyl-, cycloalkylalkynyl-, cycloalkenylalkyl-, cycloalkenylalkenyl-, cycloalkenylalkynyl-, heterocyclyl-, heterocyclylalkyl-, heterocyclylalkenyl-, heterocyclylalkynyl-, RG2dO-L-, RG2dS-L-, (RG2d)2N-L-, RG2d—C(═O)-L-, RG2dO—C(═O)-L-, (RG2d)2N—C(═O)-L-, RG2d—C(═O)N(RG2e)-L-, RG2dO—C(═O)N(RG2e)-L-, (RG2d)2N—C(═O)N(RG2e)-L-, RG2d—C(═O)O-L, (RG2d)2N—C(═O)O-L-, RG2d—S(═O)2-L-, (RG2d)2N—S(═O)2-L-, RG2d—S(═O)2N(RG2e)-L-, (RG2d)2N—S(═O)2N(RG2e)-L-, aryl-, arylalkyl-, arylcycloalkyl-, aryloxy-, aryloxyalkyl-, aryloxycycloalkyl-, heteroaryl-, heteroarylalkyl-, heteroarylcycloalkyl, heteroaryloxy-, heteroaryloxyalkyl-, and heteroaryloxycycloalkyl-
• either of which may be optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, oxo, —NH2, —SO2NH2, —SONH2, —CONH2
• RG2d and RG2e independently at each occurrence are selected from the group consisting of alkyl-, heteroalkyl-, alkenyl-, alkynyl-, cycloalkyl-, heterocyclyl-, cyclolalkylalkyl-, heterocyclylalkyl-, aryl-, arylalkyl-, heteroaryl-, and heteroarylalkyl-
• either of which may be optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, oxo, —NH2, —SO2NH2, —SONH2, —CONH2
• G3 is selected from the group consisting of alkyl-, heteroalkyl-, alkenyl-, alkynyl-, cycloalkyl-, cycloalkenyl-, cycloalkynyl-, heterocyclyl-, cycloalkylalkyl-, heterocyclylalkyl-, aryl-, aryloxy-, arylalkyl-, arylalkyloxy-, aryloxyalkyl-, aryloxyalkyloxy-, heteroaryl-, heteroaryloxy-, heteroarylalkyl-, heteroarylalkyloxy-, heteroaryloxyalkyl-, heteroaryloxyalkyloxy- either of which may be optionally substituted with one or more RG3c;
• RG3a and RG3b independently at each occurrence are selected from the group consisting of hydrogen, alkyl-, heteroalkyl-, alkenyl-, alkynyl-, cycloalkyl-, heterocyclyl-, aryl- and heteroaryl- either of which may be optionally substituted with one or more RG3c;
• or in the case where two RG3as are attached to the same N, they may together with the N atom to which they are attached form a heterocycle which may be optionally substituted with one or more RG3c;
• RG3c is selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, oxo, —NH2, —SO2NH2, —SONH2, —CONH2
• or RG3c is selected from the group consisting of alkyl-, heteroalkyl-, cycloalkyl-, alkenyl-, alkynyl-, alkenylalkyl-, alkynylalkyl-, cycloalkenyl-, cycloalkylalkyl-, cycloalkylalkenyl-, cycloalkylalkynyl-, cycloalkenylalkyl-, cycloalkenylalkenyl-, cycloalkenylalkynyl-, heterocyclyl-, heterocyclylalkyl-, heterocyclylalkenyl-, heterocyclylalkynyl-, RG3dO-L-, RG3dS-L-, (RG3d)2N-L-, RG3d—C(═O)-L-, RG3dO—C(═O)-L-, (RG3d)2N—C(═O)-L-, RG3d—C(═O)N(RG3e)-L-, RG3dO—C(═O)N(RG3e)-L-, (RG3d)2N—C(═O)N(RG3e)-L-, RG3d—C(═O)O-L-, (RG3d)2N—C(═O)O-L-, RG3d—S(═O)2-L-, (RG3d)2N—S(═O)2-L-, RG3d—S(═O)2N(RG3e)-L-, (RG3d)2N—S(═O)2N(RG3e)-L-, aryl-, arylalkyl-, arylcycloalkyl-, aryloxy-, aryloxyalkyl-, aryloxycycloalkyl-, heteroaryl-, heteroarylalkyl-, heteroarylcycloalkyl, heteroaryloxy-, heteroaryloxyalkyl-, and heteroaryloxycycloalkyl-
• either of which may be optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, oxo, —NH2, —SO2NH2, —SONH2, —CONH2
• RG3d and RG3e independently at each occurrence are selected from the group consisting of alkyl-, heteroalkyl-, alkenyl-, alkynyl-, cycloalkyl-, heterocyclyl-, cyclolalkylalkyl-, heterocyclylalkyl-, aryl-, arylalkyl-, heteroaryl-, and heteroarylalkyl-
• either of which may be optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, oxo, —NH2, —SO2NH2, —SONH2, —CONH2
• or in the case where two RG3ds are attached to the same N, they may together with the N atom to which they are attached form a heterocycle which may be optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, oxo, —NH2, —SO2NH2, —SONH2, —CONH2
• L is a covalent bond or L is independently at each occurrence selected from the group consisting of alkyl-, heteroalkyl-, cycloalkyl-, heterocyclyl-, alkylcycloalkyl-, cycloalkylalkyl-, aryl and heteroaryl;
• and pharmaceutically acceptable salts, hydrates, or solvates thereof.