US 10,457,669 B2 · Benzolactam compounds as protein kinase inhibitors

Abstract

The invention provides a compound of formula (0): or a pharmaceutically acceptable salt, N-oxide or tautomer thereof; wherein: n is 1 or 2; X is CH or N; Y is selected from CH and C—F; Z is selected from C—Rz and N; R1 is selected from: -(Alk1)t-Cyc1; wherein t is 0 or 1; Optionally substituted C1-6 acyclic hydrocarbon groups 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 optionally substituted C1-3 alkyl; and R4a is selected from hydrogen and a C1-3 alkyl group; wherein Rz, Alk1, Cyc1, L1 and R7 are defined herein; provided that the compound is other than 6-benzyl-3-{2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl}-7,8-dihydro-1,6-naphthyridin-5(6H)-one and 3-{2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl}-7,8-dihydro-1,6-naphthyridin-5(6H)-one and salts and tautomers thereof. The compounds are inhibitors of ERK1/2 kinases and will be useful in the treatment of ERK1/2-mediated conditions. The compounds are therefore useful in therapy, in particular in the treatment of cancer.

A compound selected from:

(a) a compound having the formula (2):
or a pharmaceutically acceptable salt or tautomer thereof;
and
(b) a compound having the formula (5):
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 O, 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—Hyd1 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-O and 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 O 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 NR8R9, 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.

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Benzolactam compounds as protein kinase inhibitors

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Benzolactam compounds as protein kinase inhibitors

Life of this patent

Abstract

Claims25