US 11,939,321 B2
Benzolactam compounds as protein kinase inhibitors
Valerio Berdini, Cambridge (GB); Ildiko Maria Buck, London (GB); James Edward Harvey Day, Cambridge (GB); Charlotte Mary Griffiths-Jones, Cambridge (GB); Thomas Daniel Heightman, Harpenden (GB); Steven Howard, Cambridge (GB); Christopher William Murray, Cambridge (GB); David Norton, Cambridge (GB); Marc O'Reilly, Hereford (GB); Alison Jo-Anne Woolford, Cambridge (GB); Michael Liam Cooke, Nottingham (GB); David Cousin, Nottingham (GB); Stuart Thomas Onions, Nottingham (GB); Jonathan Martin Shannon, Nottingham (GB); and John Paul Watts, Southwell (GB)
Assigned to OTSUKA PHARMACEUTICAL CO., LTD., Tokyo (JP)
Filed by OTSUKA PHARMACEUTICAL CO., LTD., Tokyo (JP)
Filed on Apr. 7, 2021, as Appl. No. 17/224,733.
Application 17/224,733 is a continuation of application No. 16/541,863, filed on Aug. 15, 2019, granted, now 11,001,575.
Application 16/541,863 is a continuation of application No. 15/767,775, granted, now 10,457,669, issued on Oct. 29, 2019, previously published as PCT/IB2016/001507, filed on Oct. 20, 2016.
Claims priority of application No. 1518676 (GB), filed on Oct. 21, 2015; and application No. 1611351 (GB), filed on Jun. 30, 2016.
Prior Publication US 2023/0019032 A1, Jan. 19, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 405/14 (2006.01); C07D 403/14 (2006.01); C07D 409/14 (2006.01); C07D 471/04 (2006.01); C07D 413/14 (2006.01); C07D 471/08 (2006.01); C07D 401/14 (2006.01); C07D 417/14 (2006.01); C07D 403/04 (2006.01); C07D 487/04 (2006.01); C07D 497/08 (2006.01); C07D 498/22 (2006.01); C07D 513/04 (2006.01); A61K 31/444 (2006.01); A61K 31/506 (2006.01); A61K 31/5377 (2006.01); A61K 31/541 (2006.01); A61K 31/55 (2006.01); A61K 31/553 (2006.01); A61P 35/00 (2006.01)
CPC C07D 405/14 (2013.01) [A61K 31/444 (2013.01); A61K 31/506 (2013.01); A61K 31/5377 (2013.01); A61K 31/541 (2013.01); A61K 31/55 (2013.01); A61K 31/553 (2013.01); A61P 35/00 (2018.01); C07D 401/14 (2013.01); C07D 403/04 (2013.01); C07D 403/14 (2013.01); C07D 409/14 (2013.01); C07D 413/14 (2013.01); C07D 417/14 (2013.01); C07D 471/04 (2013.01); C07D 471/08 (2013.01); C07D 487/04 (2013.01); C07D 497/08 (2013.01); C07D 498/22 (2013.01); C07D 513/04 (2013.01)] 28 Claims
 
1. A method for:
inhibiting the activity of ERK1/2;
(ii) treating lung cancer, melanoma, or colorectal cancer;
(iii) treating leukemia or lymphoma;
(iv) treating a haematological malignancy or condition of lymphoid lineage or of myeloid lineage;
(v) treating an adenoma or carcinoma; or
(vi) treatment of a disease state or condition selected from tumours of epithelial origin; haematological malignancies and premalignant haematological disorders and disorders of borderline malignancy; tumours of mesenchymal origin; neural crest cell-derived tumours; tumours of the central or peripheral nervous system; endocrine tumours; ocular and adnexal tumours; germ cell and trophoblastic tumours; and paediatric and embryonal tumours; or syndromes which leave the patient susceptible to malignancy;
said method comprising administering to a subject a therapeutically effective amount of a compound selected from:
(a) a compound having the formula (2):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt or tautomer thereof; and
(b) a compound having the formula (5):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt or tautomer thereof;
wherein
n is 1 or 2;
Z is selected from C—Rz and N;
Rz is selected from hydrogen; halogen; methoxy; and C1-3 alkyl optionally substituted with hydroxy or methoxy;
R1 is selected from:
(Alk1)t-Cyc1; wherein t is 0 or 1; and Alk1 is a C1-4 straight chain or branched alkylene group optionally substituted with 1 or 2 hydroxy groups; and
C1-6 acyclic hydrocarbon groups which are unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from hydroxy; oxo; fluorine; and cyano; and wherein 1 or 2 but not all of the carbon atoms of the hydrocarbon group can be replaced by O or N;
Cyc1 is a cyclic group selected from (a) 3 to 9 membered non-aromatic monocyclic and bicyclic carbocyclic and heterocyclic groups containing 0, 1, 2, or 3 heteroatom ring members selected from O, N, S, S(O) and S(O)2; (b) 5 to 6 membered monocyclic heteroaryl groups containing 1, 2 or 3 heteroatom ring members of which 1 is N and the others, when present, are selected from 0, N and S; and (c) 3 to 7 membered monocyclic carbocyclic groups; wherein each cyclic group (a), (b) and (c) is unsubstituted or substituted with 1, 2 or 3 substituents R6 selected from hydroxy; oxo; fluorine; amino; NH(Hyd1); N(Hyd1)2; O-Hyd1; —C(═O)—Hyd1; —C(═O)—O-Hyde and Hyd1; where Hyd1 is a C1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy;
R2 is selected from hydrogen; halogen; and C1-3 hydrocarbon groups optionally substituted with one or more fluorine atoms;
R3 is hydrogen or a group L1-R7;
R4 is selected from hydrogen; methoxy; and C1-3 alkyl optionally substituted with hydroxy, amino, mono- or di-C1-2 alkylamino, a cyclic amino group or methoxy; wherein the cyclic amino group is a saturated 4-7 membered heterocyclic group containing a nitrogen ring member and optionally a second heteroatom ring member selected from O, N and S, wherein the cyclic amino group is linked via a nitrogen ring member thereof to the C1-3 alkyl, and wherein the cyclic amino group is optionally substituted with one or two methyl groups; provided that no more than one R4 can be other than hydrogen or methyl;
L1 is selected from a bond; Alk2, Alk2-Oand Alk2-C(═O) wherein Alk2 is a C1-4 straight chain or branched alkylene group which is optionally substituted with one or more substituents selected from hydroxy, methoxy, amino, methylamino, dimethylamino and fluorine;
R7 is selected from:
hydrogen;
CO2H;
NR8R9;
a carbocyclic or heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; and
an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO2 or NR11;
R8 is selected from hydrogen and a C1-4 hydrocarbon group, the C1-4 hydrocarbon group being optionally substituted with 1-2 substituents selected from hydroxy, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, and 4-7 membered saturated heterocyclic rings containing 1-2 heteroatom ring members selected from 0 and N, wherein the mono-C1-4 alkylamino, di-C1-4 alkylamino, and 4-7 membered saturated heterocyclic rings are each optionally substituted with 1-2 hydroxy or C1-3 alkyl substituents;
R9 is selected from:
hydrogen;
a carbocyclic or heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; and
an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R10; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO2 or NR11;
or NR8R9 forms a heterocyclic group having from 4 to 12 ring members wherein, in addition to the nitrogen atom of N8R9, the heterocyclic group optionally contains 1 or 2 further heteroatom ring members selected from O, N and S and oxidised forms of S; and wherein the heterocyclic group is optionally substituted with one or more substituents R10;
R10 is selected from:
halogen; hydroxy; oxo; cyano;
OR12 wherein R12 is C1-6 alkyl or C3-6 cycloalkyl, each being optionally substituted with halogen;
an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having 3 to 7 ring members of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R13 selected from hydroxy; halogen; cyano; amino; —NH(Hyd1); —N(Hyd1)2; and —(O)v-Hyd1 where v is 0 or 1; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO2 or NR11; and
carbocyclic and heterocyclic groups having 3 to 7 ring members of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R13; and
R11 is selected from hydrogen and a C1-4 hydrocarbon group.