Enzyme inhibitors

A compound of formula (I):

• wherein
• *1 denotes a chiral centre
• n is 0, 1 or 2;
• A is selected from H, —(C═O)R4, —SO2R6, or —(CH2)—R13;
• Y is either a bond, or —[CHR5]-;
• R1 is H or alkylb;
• R2A is selected from H, alkyl, —(CH2)0-3aryl, —(CH2)0-3heteroaryl, —(CH2)0-3cycloalkyl, —(CH2)0-3-[benzothiophene], —(CH2)0-3-[indole], or
• or,
• when Y is a bond, R1 and R2A, together with nitrogen atom to which R1 is attached and the carbon atom to which R2A is attached, is optionally linked by alkylene to form a 4-, 5-, or 6-membered saturated heterocycle, optionally wherein the 4-, 5-, or 6-membered saturated heterocycle is optionally substituted with aryl, or wherein two adjacent carbon atoms on the 4-, 5-, or 6-membered saturated heterocycle are optionally linked to form a 6-membered aromatic ring, or wherein two adjacent carbon atoms on the 4-, 5-, or 6-membered saturated heterocycle are optionally linked to form a 3-, 4-, or 5-membered saturated hydrocarbon ring which is optionally mono- or di-substituted by alkylb;
• when Y is —[CHR5]-, R5 is H;
• or,
• when Y is —[CHR5]-, together with the carbon atoms to which each of R5 and R2A are attached, R5 and R2A is optionally linked by alkylene to form a 4-, 5-, 6-membered saturated ring;
• or,
• when Y is —[CHR5]-, together with the nitrogen atom to which R1 is attached, the carbon atom to which R5 is attached, and the carbon atom to which R2A and R2B are both attached, R5 and R1 is optionally linked by alkylene to form a saturated 4-, 5-, or 6-membered heterocycle, optionally wherein one atom on the saturated 4-, 5-, or 6-membered heterocycle is optionally linked by alkylene to join with R2A;
• R2B is H or alkylb;
• or,
• R2A and R2B, together with the carbon to which R2A and R2B are both attached, is linked by alkylene or heteroalkylene to form a 3-, 4-, 5-, or 6-membered saturated ring, optionally wherein the 3-, 4-, 5-, or 6-membered saturated ring contains one or two ring members that are selected from N or O;
• R3 is:
• (i) a fused 6,5- or 6,6-bicyclic ring, containing one heteroatom selected from S or N, wherein at least one of the rings is aromatic and, optionally the bicyclic ring contains one additional heteroatom independently selected from N, O or S;
• optionally wherein the fused 6,5- or 6,6-bicyclic ring is substituted with 1, 2, or 3 substituents selected from alkylb, alkoxy, OH, NH2, halo, CN, or CF3;
• wherein the fused 6,5-bicyclic ring is optionally attached via the 6- or 5-membered ring;
• or
• (ii) phenyl, pyridyl, or thiophenyl, which is optionally substituted with 1, 2 or 3 substituents independently selected from alkylb, alkoxy, OH, NH2 halo, CN, CF3, —C(═NH)NH2, or heteroarylb;
• wherein when n=1, and R3 is phenyl substituted with at least one —(CH2NH2), R2A is alkyl and R2B is H;
• or
• (iii)
• R4 is one of:
• (i) a group of formula (II),
• wherein -[L]- is a bond, —[(CH2)1-4]—, —[(CH2)—O—(CH2)]—, or —[O—(CH2)]—;
• and P is alkoxy, OH or NR11R12;
• wherein *2 denotes a chiral centre, and
• wherein when -[L]- is a bond, B is a C1-4 linear or branched chain hydrocarbon, and
• wherein when -[L]- is —[(CH2)1-4]—, —[(CH2)—O—(CH2)]—, or —[O—(CH2)]—, B is OH, aryl, heteroaryl, heterocyclyl, cycloalkyl or
• or,
• (ii) —(CH2)m-[fused 6,5- or 6,6-heteroaromatic bicyclic ring], wherein at least one ring atom is a heteroatom selected from O, N or S, and optionally, 1, 2 or 3 additional ring atoms are selected from N or NH;
• wherein the fused 6,5- or 6,6-heteroaromatic bicyclic ring is optionally substituted with 1, 2 or 3 alkylb;
• wherein the 6,5-heteroaromatic bicyclic ring is optionally attached to —(CH2)m— via the 6- or 5-membered ring;
• or,
• (iii) methyl, —C(CH3)2(OH), —C(CH3)2(NHMe), —(CH2)m-(aryl), —(CH2)m-(cycloalkyl), —(CH2)m-(heteroaryl), —(CH2)m-(heterocyclyl), —(CH2)-(alkyl), —(CH(halo)2), —(CH2)m—(NR8R9), —(CH2)m—(NR10R7), —(CH2)m—O—(CH2)k-(aryl), —(CH2)m—(SO2)—(CH2)k-(aryl), —(CH2)m-(alkoxy), —(CH2)m—O—(CH2)k-(heteroaryl), or —(CH2)m-[pyridone, which is optionally substituted by alkylb, or CF3];
• wherein k=0, 1, 2, or 3;
• wherein m=0, 1, 2 or 3;
• wherein:
• when Y is —[CHR5]- and R5 is H, R2A is CH2-aryl or H;
• and
• when Y is —[CHR5]-, R3 is
• when A is H, R3 is
• and
• when R3 is
• R2A is not H;
• wherein:
• R6 is alkyl or —(CH2)0-3-(aryl);
• R7 is independently selected from H, —SO2CH3, methyl, ethyl, propyl, isopropyl, or cycloalkyl;
• R8 and R9 are independently selected from H, —SO2CH3, alkylb, heteroarylb, or cycloalkyl;
• or R8 and R9 together with the nitrogen atom to which they are attached form a carbon-containing 4-, 5-, 6- or 7-membered heterocyclic ring, optionally containing an additional heteroatom selected from N, NR10, S, or O, which is saturated or unsaturated with 1 or 2 double bonds and which are optionally mono- or di-substituted with substituents independently selected from oxo, alkylb, alkoxy, OH, halo, —SO2CH3, or CF3;
• or R8 and R9 together with the nitrogen atom to which they are attached form a carbon-containing 5- or 6-membered heterocyclic ring, which is fused to an arylb or a heteroarylb;
• R10 is independently selected from H, —SO2R6, alkylb, —(CH2)0-3arylb, —(CH2)0-3heteroarylb, cycloalkyl, —(C═O)-(aryl), or —(CH2)0-3heterocyclylb;
• or R10 is a carbon-containing 4-, 5-, 6- or 7-membered heterocyclic ring, optionally containing an additional heteroatom selected from N, NR7, S, SO, SO2, or O, which is saturated or unsaturated with 1 or 2 double bonds and which is optionally mono- or di-substituted with substituents independently selected from oxo, alkylb, alkoxy, OH, halo, —SO2CH3, or CF3;
• R11 and R12 are independently selected from H, alkylb, —SO2R6, cycloalkyl, —(C═O)O-(alkylb), —(C═O)-phenyl, —CH2-phenyl, or CH2—COOH;
• or R11 and R12 together with the nitrogen atom to which they are attached form a carbon-containing 4-, 5-, 6- or 7-membered heterocyclic ring optionally containing an additional heteroatom selected from N, O, or NR10, wherein the heterocyclic ring is optionally mono- or di-substituted with substituents independently selected from alkylb, OH, halo or CF3;
• R13 is selected from heteroaryl, cycloalkyl, heterocyclyl or arylb;
• wherein:
• alkoxy is a linear O-linked hydrocarbon of between 1 and 6 carbon atoms (C1-C6) or a branched O-linked hydrocarbon of between 3 and 6 carbon atoms (C3-C6);
• alkoxy is optionally substituted with 1 or 2 substituents independently selected from OH, CN, CF3, —N(R7)2 or fluoro;
• alkyl is a linear saturated hydrocarbon having up to 6 carbon atoms (C1-C6) or a branched saturated hydrocarbon of between 3 and 6 carbon atoms (C3-C6);
• alkyl is optionally substituted with 1 or 2 substituents independently selected from (C1-C6)alkoxy, OH, —NR8R9, —NHCOCH3, —CO(heterocyclylb), —COOR8, —CONR8R9, CN, CF3, halo, oxo or heterocyclylb;
• alkylb is a linear saturated hydrocarbon having up to 6 carbon atoms (C1-C6) or a branched saturated hydrocarbon of between 3 and 6 carbon atoms (C3-C6);
• alkyl is optionally substituted with 1 or 2 substituents independently selected from (C1-C6)alkoxy, OH, —N(R7)2, —NHCOCH3, CF3, halo, oxo o cyclopropane;
• alkylene is a bivalent linear saturated hydrocarbon having 1 to 5 carbon atoms (C1-C6);
• alkylene is optionally substituted with 1 or 2 substituents independently selected from alkyl, (C1-C6)alkoxy, OH, CN, CF3 r halo;
• aryl is phenyl, biphenyl or naphthyl;
• aryl is optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, —SO2CH3, halo, —SO2NR8R9, CN, —(CH2)0-3—O-heteroarylb, arylb, —O-arylb, —(CH2)0-3-heterocyclylb, —(CH2)1-3-arylb, —(CH2)0-3-heteroarylb, —COOR8, —CONR8R9, —(CH2)0-3—NR8R9, OCF3 or CF3;
• or two adjacent carbon ring atoms on the aryl are optionally linked by a heteroalkylene to form a non-aromatic ring containing 5, 6, or 7 ring members which is optionally substituted with OH;
• or optionally wherein two adjacent ring atoms on aryl are linked to form a 5- or 6-membered aromatic ring containing 1 or 2 heteroatoms that are selected from N, NR10, S, or O;
• arylb is phenyl, biphenyl or naphthyl, which is optionally substituted with 1, 2 or 3 substituents independently selected from methyl, ethyl, propyl, isopropyl, alkoxy, OH, —SO2CH3, N(R7)2, halo, CN, or CF3;
• or two adjacent carbon ring atoms on the aryl is optionally linked by a heteroalkylene to form a non-aromatic ring containing 5, 6, or 7 ring members;
• cycloalkyl is monocyclic saturated hydrocarbon ring of between 3 and 6 carbon atoms (C3-C6);
• cycloalkyl is optionally substituted with 1 or 2 substituents independently selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, OH, CN, CF3 or halo;
• optionally wherein two adjacent ring atoms on cycloalkyl are linked to form a 5- or 6-membered saturated hydrocarbon ring;
• halo is F, Cl, Br, or I;
• heteroalkylene is a bivalent linear saturated hydrocarbon having 2 to 5 carbon atoms (C2-C5), wherein 1 or 2 of the 2 to 5 carbon atoms are replaced with NR10, S, or O;
• heteroalkylene is optionally substituted with 1 or 2 substituents independently selected from alkyl, (C1-C6)alkoxy, OH, CN, CF3 or halo;
• heteroaryl is a 5- or 6-membered carbon-containing aromatic ring containing one, two or three ring members that are selected from N, NR10, S, or O;
• heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, heteroarylb, phenyl, cycloalkyl, OH, OCF3, halo, heterocyclylb, CN, or CF3;
• heteroarylb is a 5- or 6-membered carbon-containing aromatic ring containing one, two or three ring members that are selected from N, NR10, S, or O;
• heteroarylb is optionally substituted with 1, 2 or 3 substituents independently selected from methyl, ethyl, propyl, isopropyl, alkoxy, OH, OCF3, COOCH3, COOCH2CH3, COO—(CH2)2—CH3, COO-(iPr), halo, CN, or CF3;
• heterocyclyl is a 4-, 5-, 6-, or 7-membered carbon-containing non-aromatic ring containing one, two, three, or four ring members that are selected from N, NR10, S, SO, SO2 or O;
• heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkoxy, arylb, OH, OCF3, halo, oxo, CN, NR8R9, —O(arylb), —O(heteroarylb) or CF3;
• or optionally wherein two ring atoms on heterocyclyl are linked with an alkylene to form a non-aromatic ring containing 5, 6, or 7 ring members;
• or optionally wherein two ring atoms on heterocyclyl are linked with an heteroalkylene to form a non-aromatic ring containing 5, 6, or 7 ring members;
• or optionally wherein two adjacent ring atoms on heterocyclyl are linked to form a 5- or 6-membered aromatic ring which optionally contains 1 or 2 heteroatoms that are selected from N, NR10, S, or O;
• heterocyclylb is a 4-, 5-, 6-, or 7-membered carbon-containing non-aromatic ring containing one, two or three ring members that are selected from N, NR7, S, SO, S02 or O;
• heterocyclylb is optionally substituted with 1, 2, 3, or 4 substituents independently selected from methyl, ethyl, propyl, isopropyl, alkoxy, OH, OCF3, halo, oxo, CN, or CF3;
• or a tautomer, isomer, stereoisomer, deuterated isotope, pharmaceutically acceptable salt and/or solvate thereof.