Pyrrolo[2,3-b]pyridine derivative and use thereof for treatment of cancer
The present invention provides a fused heterocycle derivative having a strong Smo inhibitory activity, and use thereof. Specially, the present invention relates to a compound represented by the formula wherein each symbol is as defined in the specification, or salt thereof, and a medicament containing the compound or a prodrug thereof, which is an Smo inhibitor or an agent for the prophylaxis or treatment of cancer.
1. A compound represented by formula (AI-b):
wherein
X A is NR A1 wherein R A1 is hydrogen or a C 1-6 alkyl group,
Y A is nitrogen,
Z A is CR A4 wherein R A4 is hydrogen, halogen, an amino group optionally having substituent(s) or a mercapto group optionally having a substituent,
R A2 is a carbamoyl group optionally having substituent(s),
R A3 is a substituted hydroxy group,
R A5 is a C 1-6 alkyl group having substituent(s) selected from Substituent A Group below, an amino group optionally having substituent(s), a cyclic group optionally having substituent(s), or a hydroxy group substituted by a cyclic group optionally having substituent(s), and
R A6 is a C 1-6 alkyl group optionally having substituent(s) selected from the Substituent A Group, or a pharmaceutically acceptable salt thereof,
wherein
(i) the amino group optionally having substituent(s) is an amino group optionally having 1 or 2 substituents selected from the group consisting of
(1) a C 1-6 alkyl group optionally having substituent(s) selected from Substituent A Group,
(2) a C 2-6 alkenyl group optionally having substituent(s) selected from the Substituent A Group,
(3) a C 2-6 alkynyl group optionally having substituent(s) selected from the Substituent A Group,
(4) a C 1-6 alkoxy group optionally having substituent(s) selected from the Substituent A Group,
(5) a C 1-6 alkyl-carbonyl group optionally having substituent(s) selected from the Substituent A Group,
(6) a C 3-8 cycloalkyl group optionally having substituent(s) selected from Substituent C Group below,
(7) a C 6-10 aryl group optionally having substituent(s) selected from Substituent B Group below,
(8) a C 6-10 aryl-carbonyl group optionally having substituent(s) selected from the Substituent B Group,
(9) an aromatic heterocyclic group optionally having substituent(s) selected from the Substituent B Group,
(10) a non-aromatic heterocyclic group optionally having substituent(s) selected from the Substituent C Group,
(11) an aromatic optionally having substituent(s) selected from the Substituent B Group, and
(12) a non-aromatic heterocyclyl-carbonyl group optionally having substituent(s) selected from the Substituent C Group,
(ii) the mercapto group optionally having a substituent is a mercapto group optionally substituted by a substituent selected from the group consisting of
(1) a C 1-6 alkyl group optionally having substituent(s) selected from the Substituent A Group,
(2) a C 2-6 alkenyl group optionally having substituent(s) selected from the Substituent A Group,
(3) a C 2-6 alkynyl group optionally having substituent(s) selected from the Substituent A Group,
(4) a C 1-6 alkoxy group optionally having substituent(s) selected from the Substituent A Group,
(5) a C 1-6 alkyl-carbonyl group optionally having substituent(s) selected from the Substituent A Group,
(6) a C 3-8 cycloalkyl group optionally having substituent(s) selected from the Substituent C Group,
(7) a C 6-10 aryl optionally having substituent(s) selected from the Substituent B Group,
(8) a C 6-10 aryl-carbonyl group optionally having substituent(s) selected from the Substituent B Group,
(9) an aromatic heterocyclic group optionally having substituent(s) selected from the Substituent B Group,
(10) a non-aromatic heterocyclic group optionally having substituent(s) selected from the Substituent C Group,
(11) an aromatic heterocyclyl-carbonyl group optionally having substituent(s) selected from the Substituent B Group, and
(12) a non-aromatic heterocyclyl-carbonyl group optionally having substituent(s) selected from the Substituent C Group,
(iii) the carbamoyl group optionally having substituent(s) is a carbamoyl group optionally having 1 or 2 substituents selected from the group consisting of
(1) a C 1-6 alkyl group optionally having substituent(s) selected from the Substituent A Group,
(2) a C 2-6 alkenyl group optionally having substituent(s) selected from the Substituent A Group,
(3) a C 2-6 alkenyl group optionally having substituent(s) selected from the Substituent A Group,
(4) a C 1-6 alkoxy group optionally having substituent(s) selected from the Substituent A Group,
(5) a C 1-6 alkyl-carbonyl group optionally having substituent(s) selected from the Substituent A Group,
(6) a C 3-8 cycloalkyl group optionally having substituent(s) selected from the Substituent C Group,
(7) a C 6-10 aryl group optionally having substituent(s) selected from the Substituent B Group,
(8) a C 6-10 aryl-carbonyl group optionally having substituent(s) selected from the Substituent B Group;
(9) an aromatic heterocyclic group optionally having substituent(s) selected from the Substituent B Group,
(10) a non-aromatic heterocyclic group optionally having substituent(s) selected from the Substituent C Group,
(11) an aromatic heterocycyl-carbonyl group optionally having substituent(s) selected from the Substituent B Group, and
(12) a non-aromatic heterocyclyl-carbonyl group optionally having substituent(s) selected from the Substituent C Group,
(iv) the substituted hydroxy group is a hydroxy group substituted by a substituent selected from the group consisting of
(1) a C 1-6 alkyl group optionally having substituent(s) selected from the Substituent A Group,
(2) a C 2-6 alkenyl group optionally having substituent(s) selected from the Substituent A Group,
(3) a C 2-6 alkynyl group optionally having substituent(s) selected from the Substituent A Group,
(4) a C 1-6 alkoxy group optionally having substituent(s) selected from the Substituent A Group,
(5) a C 1-6 alkyl-carbonyl group optionally having substituent(s) selected from the Substituent A Group,
(6) a C 3-8 cycloalkyl group optionally having substituent(s) selected from the Substituent C Group,
(7) a C 6-10 aryl group optionally having substituent(s) selected from the Substituent B Group,
(8) a C 6-10 aryl-carbonyl group optionally having substituent(s) selected from the Substituent B Group,
(9) an aromatic heterocyclic group optionally having substituent(s) selected from the Substituent B Group,
(10) a non-aromatic heterocyclic group optionally having substituent(s) selected from the Substituent C Group,
(11) an aromatic heterocyclyl-carbonyl group optionally having substituent(s) selected from the Substituent B Group, and
(12) a non-aromatic heterocyclyl-carbonyl group optionally having substituent(s) selected from the Substituent C Group, and
(v) the cyclic group optionally having substituent(s) is selected from the group consisting of
(1) a C 3-8 cycloalkyl group optionally having substituent(s) selected from the Substituent C Group,
(2) a group derived from a fused ring wherein a C 3-8 cycloalkane and a benzene ring are condensed, which optionally has substituent(s) selected from the Substituent C Group,
(3) a C 6-10 aryl group optionally having substituent(s) selected from the Substituent B Group,
(4) an aromatic heterocyclic substituent(s) selected from the Substituent B Group, and
(5) a non-aromatic heterocyclic group optionally having substituent(s) selected from the Substituent C Group,
wherein the Substituent A group consists of:
(1) halogen;
(2) a cyano group;
(3) a nitro group;
(4) a hydroxy group;
(5) a carboxy group;
(6) a C 3-8 cycloalkyl group optionally having 1 to 3 substituents selected from the group consisting of
(a) halogen,
(b) a hydroxy group,
(c) a C 1-6 alkyl group optionally having 1 to 3 halogen atoms,
(d) a C 1-6 alkoxy group optionally having 1 to 3 halogen atoms, and
(e) an oxo group;
(7) a C 6-10 aryl group optionally having 1 to 3 substituents selected from the group consisting of
(a) halogen,
(b) a hydroxy group,
(c) a C 1-6 alkyl group optionally having 1 to 3 halogen atoms, and
(d) a C 1-6 alkoxy group optionally having 1 to 3 halogen atoms;
(8) a 5- to 12-membered aromatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of
(a) halogen,
(b) a hydroxy group,
(c) a C 1-6 alkyl group and
(d) a C 1-6 alkoxy group optionally having 1 to 3 halogen atoms;
(9) a 4- to 12-membered non-aromatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of
(a) halogen,
(b) a hydroxy group,
(c) a C 1-6 alkyl group optionally having 1 to 3 halogen atoms,
(d) a C 1-6 alkoxy group optionally having 1 to 3 halogen atoms,
(e) a C 1-6 alkyl-carbonyl group optionally having 1 to 3 hydroxy, and
(f) an oxo group;
(10) an amino group optionally having 1 or 2 substituents selected from the group consisting of
(a) a C 1-6 alkyl group optionally having 1 to 3 halogen atoms,
(b) a C 1-6 alkyl-carbonyl group optionally having 1 to 3 substituents selected from the group consisting of
(i) halogen,
(ii) a hydroxy group, and
(iii) a C 6-10 aryl group,
(c) a C 1-6 alkoxy-carbonyl group optionally having 1 to 3 substituents selected from the group consisting of
(i) halogen and
(ii) a C 6-10 aryl group,
(d) a C 1-6 alkylsulfonyl group optionally having 1 to 3 substituents selected from the group consisting of
(i) halogen and
(ii) a C 6-10 aryl group,
(e) a C 6-10 arylsulfonyl group,
(f) a carbamoyl group optionally having 1 or 2 C 1-6 alkyl groups optionally having 1 to 3 halogen atoms,
(g) a 5- to 12-membered aromatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of
(i) a C 1-6 alkyl group optionally having 1 to 3 halogen atoms,
(ii) a hydroxy group,
(iii) a C 1-6 alkoxy group optionally having 1 to 3 halogen atoms, and
(iv) halogen, and
(h) a 4- to 12-membered non-aromatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of
(i) a C 1-6 alkyl group optionally to 3 halogen atoms,
(ii) a hydroxy group,
(iii) a C 1-6 alkoxy group optionally having 1 to 3 halogen atoms,
(iv) halogen, and
(v) an oxo group;
(11) an imino group;
(12) a C 1-6 alkyl-carbonyl group optionally having 1 to 3 halogen atoms;
(13) a C 1-6 alkoxy-carbonyl group optionally having 1 to 3 substituents selected from the group consisting of
(a) halogen,
(b) a C 1-6 alkoxy group,
(c) a C 6-10 aryl group,
(d) a 5- to 12-membered aromatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of
(i) a C 1-6 alkyl group optionally having 1 to 3 halogen atoms,
(ii) a hydroxy group,
(iii) a C 1-6 alkoxy group optionally having 1 to 3 halogen atoms, and
(iv) halogen, and
(e) a 4- to 12-membered non-aromatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of
(i) a C 1-6 alkyl group optionally en atoms,
(ii) a hydroxy group,
(iii) a C 1-6 alkoxy group optionally having 1 to 3 halogen atoms,
(iv) halogen, and
(v) an oxo group;
(14) a C 1-6 alkylsulfonyl group optionally having 1 to 3 substituents selected from the group consisting of
(a) halogen and
(b) a C 1-6 alkoxy group;
(15) a C 6-10 arylsulfonyl group;
(16) a carbamoyl group optionally having 1 or 2 substituents selected from the group consisting of
(a) a C 1-6 alkyl group optionally having 1 to 3 halogen atoms and
(b) C 6-10 aryl group;
(17) a thiocarbamoyl group optionally having 1 or 2 C 1-6 alkyl groups optionally having 1 to 3 halogen atoms;
(18) a sulfamoyl group optionally having 1 or 2 C 1-6 alkyl groups optionally having 1 to 3 halogen atoms;
(19) C 1-6 alkoxy group optionally having 1 to 3 substituents selected from the group consisting of
(a) halogen,
(b) a carboxy group,
(c) a C 1-6 alkoxy group,
(d) a C 1-6 alkoxy-carbonyl group optionally having 1 to 3 C 6-10 aryl groups,
(e) an amino group optionally having 1 or 2 substituents selected from a C 1-6 alkyl group and a C 1-6 alkoxy-carbonyl group,
(f) a C 3-8 cycloalkyl group,
(g) a 5- to 12-membered aromatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of
(i) halogen,
(ii) a hydroxy group,
(iii) a C 1-6 alkyl group optionally having 1 to 3 halogen atoms, and
(iv) a C 1-6 alkoxy group optionally having 1 to 3 halogen atoms, and
(h) a 4- to 12-membered non-aromatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of
(i) halogen,
(ii) a hydroxy group,
(iii) a C 1-6 alkyl group optionally having 1 to 3 halogen atoms,
(iv) a C 1-6 alkoxy group optionally en atoms, and
(v) an oxo group;
(20) a C 2-6 alkenyloxy group optionally having 1 to 3 halogen atoms;
(21) a C 3-8 cycloalkyloxy group optionally having 1 to 3 substituents selected from the group consisting of
(a) halogen and
(b) a C 1-6 alkoxy group;
(22) a C 6-10 aryloxy group;
(23) a C 7-13 aralkyloxy group;
(24) a C 1-6 alkyl-carbonyloxy group;
(25) a C 6-10 aryl-carbonyl group optionally having 1 to 3 substituents selected from the group consisting of
(a) halogen and
(b) a C 1-6 alkyl group optionally having 1 to 3 halogen atoms;
(26) a 5- to 12-membered aromatic heterocyclyl-carbonyl group optionally having 1 to 3 substituents selected from a C 1-6 alkyl group optionally having 1 to 3 halogen atoms;
(27) a 4- to 12-membered non-aromatic heterocyclyl-carbonyl group optionally substituents selected from a C 1-6 alkyl group optionally having 1 to 3 halogen atoms;
(28) a C 3-8 cycloalkyl-carbonyl group;
(29) a C 7-13 aralkyloxy-carbonyl group;
(30) a mercapto group;
(31) a C 1-6 alkylthio group optionally having 1 to 3 substituents selected from the group consisting of
(a) halogen and
(b) a C 1-6 alkoxy-carbonyl group;
(32) a C 7-13 aralkylthio group;
(33) a C 6-10 arylthio group;
(34) a C 1-3 alkyleneoxy group; and
(35) a C 1-3 alkylenedioxy group,
wherein the Substituent B Group consists of:
(1) a substituent selected from the Substituent A Group;
(2) a C 1-6 alkyl group optionally having 1 to 3 substituents selected from the group consisting of
(a) halogen,
(b) a hydroxy group,
(c) a carboxy group,
(d) a C 1-6 alkoxy group,
(e) a C 1-6 alkoxy-carbonyl group,
(f) an amino group optionally having 1 or 2 C 1-6 alkyl groups, and
(g) a C 6-10 aryl-carbonyl group;
(3) a C 2-6 alkenyl group optionally having 1 to 3 substituents selected from the group consisting of
(a) halogen,
(b) a hydroxy group,
(c) a carboxy group,
(d) a C 1-6 alkoxy group,
(e) a C 1-6 alkoxy-carbonyl group, and
(f) an amino group optionally having 1 or 2 C 1-6 alkyl groups; and
(4) a C 7-13 aralkyl group optionally having 1 to 3 substituents selected from the group consisting of
(a) halogen,
(b) a hydroxy group,
(c) a C 1-6 alkyl group optionally having 1 to 3 halogen atoms, and
(d) a C 1-6 alkoxy group,
wherein the Substituent C Group consists of:
(1) a substituent selected from the Substituent A Group;
(2) a C 1-6 alkyl group optionally having 1 to 3 substituents selected from the group consisting of
(a) halogen,
(b) a hydroxy group,
(c) a carboxy group,
(d) a C 1-6 alkoxy group,
(e) a C 1-6 alkoxy-carbonyl group,
(f) an amino group optionally having 1 or 2 C 1-6 alkyl groups, and
(g) a C 6-10 aryl-carbonyl group,
(3) a C 2-6 alkenyl group optionally to 3 substituents selected from the group consisting of
(a) halogen,
(b) a hydroxy group,
(c) a carboxy group,
(d) a C 1-6 alkoxy group,
(e) a C 1-6 alkoxy-carbonyl group, and
(f) an amino group optionally having 1 or 2 C 1-6 alkyl groups;
(4) a C 7-13 aralkyl group optionally having 1 to 3 substituents selected from the group consisting of
(a) halogen,
(b) a hydroxy group,
(c) a C 1-6 alkyl group optionally having 1 to 3 halogen atoms, and
(d) a C 1-6 alkoxy group; and
(5) an oxo group.
2. The compound or the pharmaceutically acceptable salt thereof according to claim 1 , wherein
X A is NR A1 , wherein R A1 is methyl,
Z A is CR A4 , wherein R A4 is hydrogen,
R A2 is a carbamoyl group optionally having 1 or 2 substituents selected from the group consisting of
(1) the C 1-6 alkyl group optionally having substituent(s) selected from the Substituent A Group,
(2) the C 3-8 cycloalkyl group optionally having substituent(s) selected from the Substituent C Group,
(3) the aromatic heterocyclic group optionally having substituent(s) selected from the Substituent B Group, and
(4) the non-aromatic heterocyclic group optionally having substituent(s) selected from the Substituent C Group,
R A3 is the optionally halogenated C 1-6 alkoxy group,
R A5 is
(1) the C 1-6 alkyl group having substituent(s) selected from the Substituent A Group,
(2) the amino group optionally having substituent(s),
(3) a C 6-10 aryl group optionally having substituent(s) selected from the Substituent B Group,
(4) the aromatic heterocyclic group optionally having substituent(s) selected from the Substituent B group, or
(5) the non-aromatic heterocyclic group optionally having substituent(s) selected from the Substituent C Group, and
R A6 is a C 1-6 alkyl group.
3. A pharmaceutical composition comprising the compound according to claim 1 , or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
4. A method of inhibiting smoothened in a mammal, which comprises administering to said mammal an effective amount of the compound according to claim 1 , or the pharmaceutically acceptable salt thereof.
5. A compound 6-ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-3-(1-methylethoxy)-5-[(phenylcarbonyl)amino]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising the compound according to claim 5 , or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
7. A method of inhibiting smoothened in a mammal, which comprises administering to said mammal an effective amount of the compound according to claim 5 , or the pharmaceutically acceptable salt thereof.