US 9,808,466 B2
Macrocyclic compounds as protein kinase inhibitors
Joaquín Pastor Fernández, Madrid (ES); Rosa María Álvarez Escobar, Madrid (ES); Rosario Concepción Riesco Fagundo, Madrid (ES); Ana Belén García García, Madrid (ES); Antonio Rodríguez Hergueta, Madrid (ES); Jose Ignacio Martín Hernando, Madrid (ES); Carmen Blanco Aparicio, Madrid (ES); and David Álvaro Cebrián Muñoz, Madrid (ES)
Assigned to Fundación Centro Nacional de Investigaciones Oncologicas Carlos III
Filed by Fundación Centro Nacional de Investigaciones Oncologicas Carlos III, Madrid (ES)
Filed on Jan. 26, 2016, as Appl. No. 15/6,755.
Application 15/006,755 is a continuation of application No. 14/118,009, granted, now 9,284,334, previously published as PCT/GB2012/051134, filed on May 18, 2012.
Claims priority of application No. 11382158 (EP), filed on May 19, 2011; and application No. 12275024 (EP), filed on Mar. 9, 2012.
Prior Publication US 2016/0296528 A1, Oct. 13, 2016
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 45/06 (2006.01); A61K 31/5383 (2006.01); C07D 513/16 (2006.01); C07D 513/22 (2006.01); C07D 515/22 (2006.01); A61K 31/4375 (2006.01); A61K 31/439 (2006.01); A61K 31/4745 (2006.01); A61K 31/5025 (2006.01); A61K 31/519 (2006.01)
CPC A61K 31/5383 (2013.01) [A61K 31/439 (2013.01); A61K 31/4375 (2013.01); A61K 31/4745 (2013.01); A61K 31/5025 (2013.01); A61K 31/519 (2013.01); A61K 45/06 (2013.01); C07D 513/16 (2013.01); C07D 513/22 (2013.01); C07D 515/22 (2013.01)] 9 Claims
 
1. A method of treatment of a cancer, by administering to a patient suffering from, or susceptible to the cancer, wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, colon cancer, liver cancer, lung cancer, ovary cancer, pancreatic cancer, stomach cancer, cervical cancer, prostate cancer, squamous cell carcinoma, glioblastoma, melanoma, colon-rectum cancer, oral cancer, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkett's lymphoma; hematopoietic tumors of myeloid lineage, and tumors of the central and peripheral nervous system,
which method comprises administration of a therapeutically effective amount of a compound of formula I:

OG Complex Work Unit Drawing
wherein:
ring A and ring B represent a fused bicyclic group of any one of the following formulae:

OG Complex Work Unit Drawing
wherein
in formula IA: W1a is CH, CF or N; W2a is CH, CF or N; W3a is CR4a or N; W4a is CR5a or N; W5a is CR6a or N;
in formula IB: W1b is CH, CF or N; W2b is CH, CF or N; W3b is CR4b or N; W4b is C or N; W5b is CR6b or N; W6b is C or N; W7b is C or N, and wherein when W3b represents N, W4b and W6b represent C and W5b represents C or N, then R* is hydrogen (in all other cases R* is absent);
in formula IC: W1c is CH, CRt1, N, NRq1, O or S; W2c is CH, CRt2, N, NRq2, O or S; W3c is C or N; W4c is CR5c or N; W5c is CR6c or N; W6C is C or N;
in formula ID: W1d is CH, CRt3, N, NRq3, O or S; W2d is CH, CRt4, N, NRq4, O or S; W3d is C or N; W4d is CR5d or N; W5d is C or N; W6d is C or N;
each Rt1, Rt2, Rt3, and Rt4 is independently selected from halo, C1-3 alkyl or C3 cycloalkyl, a 3- to 5-membered heterocycloalkyl group, —ORs1, —CN, —N(Rs2)Rs3, —S(O)w1 CH3 or —C(O)CH3;
w1 represents 0, 1 or 2;
each Rs1, Rs2 and R3s independently represent hydrogen or C1-2 alkyl;
each Rq1, Rq2, Rq3 and Rq4 is independently selected from C1-3 alkyl or C3 cycloalkyl, a 3- to 5-membered heterocycloalkyl group or —C(O)CH3;
each R1, R2a, R2b, R2c, R3, R4a, R5a, R6a, R4b, R6b, R5c, R6c, and R5d are independently selected from hydrogen or a substituent selected from halo, —CN, —C(O)N(Rf1)Rf2, —C(O)Rf3, —N(Rf4)Rf5, —C(O)ORf6, —ORf7, —OC(O)—Rf8, —S(O)w2CH3, C1-8 alkyl, C3-8 cycloalkyl and a 3- to 8-membered heterocycloalkyl groups, which latter three groups are optionally substituted by one or more substituents selected from ═O and E1;
w2 represents 0, 1 or 2;
Rf1, Rf2, Rf4, Rf5 and Rf7 independently represent hydrogen, C1-6 alkyl or C3-6 cycloalkyl optionally substituted by one or more substituents selected from ═O and E2; or Rf1 and Rf2 and/or Rf4 and Rf5 may be linked together to form a 4- to 8- membered ring optionally substituted by one or more substituents selected from C1-3 alkyl, C3 cycloalkyl and halo;
Rf3, Rf6 and Rf8 independently represent C1-6 alkyl or C3-6 cycloalkyl optionally substituted by one or more substituents selected from ═O and E2;
X represents a direct bond, —C(Ra)(Rb)—, —O—, —S—, —N(Rc)—, —N(Rd)C(O)—, —C(O)N(Re)—or —N(Rf)—C(O)—N(Rg)—;
Y represents -arylene-, -heteroarylene- (which latter two groups are optionally substituted by one or more substituents selected from E3), -heterocycloalkylene- or —C1-12alkylene- (which latter two groups are optionally substituted by one or more substituents selected from ═O and E4);
RN represents hydrogen or C1-6 alkyl optionally substituted by one or more substituents selected from ═O and E5;
Z represents -(Ax)1-7-, wherein each Ax independently represents —C(Rx1)(Rx2)—, —N(Rx3)—, —C(O)—, —O—, —S—, —S(O)— or —S(O)2—;
Rx1, Rx2 and Rx3 each independently represent hydrogen or a substituent selected from Ex;
each Ex independently represents halo, —C(O)Ry1, —N(Ry2)—C(O)—N(Ry3)(Ry4), C1-6 alkyl or heterocycloalkyl (both of which latter two groups are optionally substituted by one or more halo atoms);
Ry1, Ry2, Ry3 and Ry4 each independently represent hydrogen or C1-3 alkyl optionally substituted by one or more halo atoms;
each Ra, Rb, Rc, Rd, Re, Rf and Rg independently represent hydrogen, C1-6 alkyl or C3-6 cycloalkyl optionally substituted by one or more halo atoms;
each E1, E2, E3, E4 and E5 independently represents, on each occasion when used herein:
(i) Q4;
(ii) C1-12 alkyl or C3-12 cycloalkyl or heterocycloalkyl, each of which is optionally substituted by one or more substituents selected from ═O and Q5;
any two E1, E2, E3, E4 and/or E5 groups, may be linked together to form a 3- to 12-membered ring, optionally containing one or more unsaturations, and which ring is optionally substituted by one or more substituents selected from ═O and J1;
each Q4 and Q5 independently represent, on each occasion when used herein:
halo, —CN, —N(R20)R21, —OR20, —C(═Y1)—R20, —C(═Y1)—OR20, —C(═Y1)N(R20)R21, —C(═Y1)N(R20)—O—R21a, —OC(═Y1)—R20, —OC(═Y1)—OR20, —OC(═Y1)N(R20)R21, —OS(O)2OR20, —OP(═Y1)(OR20)(OR21), —OP(OR20)(OR21), —N(R22)C(═Y1)R21, —N(R22)C(═Y1)OR21, —N(R22)C(═Y1)N(R20)R21, —NR22S(O)2 R20, —NR22S(O)2N(R20)R21, —S(O)2N(R20)R21, —SC(═Y1)R20, —SC(═Y1)OR20, —SC(═Y1)N(R20)R21, —S(O)2R20, —SR20, —S(O)R20, —S(O)2OR20, C1-6 alkyl, C3-6 cycloalkyl or heterocycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from ═O and J2);
each Y1 independently represents, on each occasion when used herein, ═O, ═S, ═NR23 or ═N—CN;
each R21a represents C1-6 alkyl, C3-6 cycloalkyl or heterocycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from J4 and ═O);
each R20, R21, R22 and R23 independently represent, on each occasion when used herein, hydrogen, C1-6 alkyl, C3-6 cycloalkyl or heterocycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from J4 and ═O); or
any relevant pair of R20, R21 and R22, may be linked together to form a 4- to 20- membered ring, optionally containing one or more heteroatoms, optionally containing one or more unsaturations, and which ring is optionally substituted by one or more substituents selected from J6 and ═O;
each J1, J2, J4 and J6 independently represents, on each occasion when used herein:
(i) Q7;
(ii) C1-6 alkyl, C3-6 cycloalkyl or heterocycloalkyl, each of which is optionally substituted by one or more substituents selected from ═O and Q8;
each Q7 and Q8 independently represents, on each occasion when used herein:
halo, —CN, —N(R50)R51, —OR50, —C(═Ya)—R50, —C(═Ya)—OR50, —C(═Ya)N(R50)R51, —N(R52)C(═Ya)R51, —NR52S(O)2R50, —S(O)2N(R50)R51, —N(R52)—C(═Ya)—N(R50)R51, —S(O)2R50, —SR50, —S(O)R50, Cl-6 alkyl or C3-6 cycloalkyl (optionally substituted by one or more fluoro atoms) or heterocycloalkyl (optionally substituted by one or more substituents selected from halo, —OR60 and —N(R61)R62);
each Ya independently represents, on each occasion when used herein, ═O, ═S, ═NR53 or ═N—CN;
each R50, R51, R52 and R53 independently represents, on each occasion when used herein, hydrogen, C1-6 alkyl, or C3-6 cycloalkyl optionally substituted by one or more substituents selected from fluoro, —OR60 and —N(R61)R62; or
any relevant pair of R50, R51 and R52 may be linked together to form, a 3- to 8-membered ring, optionally containing one or more heteroatoms, optionally containing one or more unsaturations, and which ring is optionally substituted by one or more substituents selected from ═O and C1-3 alkyl;
R60, R61 and R62 independently represent hydrogen, C1-6 alkyl, or C3-6 cycloalkyl optionally substituted by one or more fluoro atoms;
wherein any heterocycloalkyl group may be selected from non-aromatic monocyclic and bicyclic heterocycloalkyl groups in which one to four of the atoms in the ring system is a heteroatom selected from N, O or S, and in which the total number of atoms in the ring system is from five to ten, wherein the heterocycloalkyl group may be bridged, and wherein the heterocycloalkyl group may be saturated or unsaturated containing one or more double and/or triple bonds,
wherein any heteroaryl group may be selected from an aromatic group containing one to four heteroatom(s) selected from N, O or S, wherein the heteroaryl group comprises five to ten atoms in the ring system, and wherein the heteroaryl group is monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic, and that when the heteroaryl group is bicyclic or tricyclic it is linked to the rest of the molecule via an aromatic ring,
or a pharmaceutically acceptable salt thereof.