Derivatives of thienopyrrole as gnrh antagonists

A compound of Formula (I),

• wherein:
• R1 is selected from:
• hydrogen, optionally substituted C1-6alkyl, optionally substituted aryl or optionally substituted arylC1-6alkyl, wherein the optional substituents are selected from C1-4alkyl, C1-4alkoxy, nitro, cyano and fluoro;
• R2 is hydrogen, optionally substituted C1-6alkyl or an optionally substituted mono or bi-cyclic aromatic ring, wherein the optional substituents are 1, 2 or 3 substituents independently selected from:
• cyano, ReRfN—, C1-6alkyl, C1-6alkoxy, halo, haloC1-6alkyl or haloC1-6alkoxy wherein Re and Rf are independently selected from hydrogen, C1-6alkyl or aryl;
• R3 is selected from a group of Formula (IIa) to Formula (IId):
• R4 is selected from hydrogen, C1-4alkyl or halo;
• R5 is a group of the formula
• wherein:
• het represents a heteroaryl ring, optionally substituted by from 1 to 2 groups selected from R12 and R13;
• and
• Q is selected from a direct bond or —[C(R15R15a)]1-2—
• each R15 and R15a are independently selected from:
• (i) hydrogen or optionally substituted C1-8alkyl, wherein the optional substituents are selected from R12;
• or
• (ii) R15 and R15a together with the carbon to which they are attached form an optionally substituted 3 to 7-membered cycloalkyl ring, wherein the optional substituents are selected from R12;
• R6 and R6a are independently selected from hydrogen, fluoro, optionally substituted C1-6alkyl, C1-6alkoxy, N—C1-6alkylamino and N,N-diC1-6alkylamino or R6 and R6a taken together and the carbon atom to which they are attached form a carbocyclic ring of 3-7 atoms or R6 and R6a taken together and the carbon atom to which they are attached form a carbonyl group;
• or when A is not a direct bond the group
• forms a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring containing one or more heteroatoms;
• or the group
• forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms;
• R7 is selected from:
• hydrogen or C1-6alkyl;
• R8 is selected from:
• (i) hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, C1-4alkoxyC1-4alkyl, hydroxy, hydroxyC1-6alkyl, cyano, N—C1-4alkylamino, N,N-di-C1-4alkylamino, C1-6alkyl-S(On)—, —O—Rb, —NRbRc, —C(O)—Rb, —C(O)O—Rb, —CONRbRc, NH—C(O)—Rb or —S(On)NRbRc, where Rb and Rc are independently selected from hydrogen and C1-6alkyl (e.g. C1-4alkyl) optionally substituted with hydroxy, amino, N—C1-4alkylamino, N,N-di-C1-4alkylamino, HO—C2-4alkyl-NH— or HO—C2-4alkyl-N(C1-4alkyl)-;
• (ii) nitro when B is a group of Formula (IV) and X is CH and p is 0;
• (iii) carbocyclyl (such as C3-7cycloalkyl or aryl) or arylC1-6alkyl each of which is optionally substituted by R12 or R13;
• (iv) heterocyclyl or heterocyclylC1-6alkyl each of which is optionally substituted by up to 4 substituents independently selected from R12 or R13 and where any nitrogen atoms within a heterocyclyl group are, where chemically allowed, optionally in their oxidised (N→O, N—OH) state;
• R12 is independently selected from:
• halo, hydroxy, hydroxyC1-6alkyl, oxo, cyano, cyanoC1-6alkyl, nitro, carboxyl, C1-6alkyl, C1-6alkoxy, C1-6alkoxyC1-4alkyl, C1-6alkoxycarbonylC0-4alkyl, C1-6alkanoylC0-4alkyl, C1-6alkanoyloxyC0-4alkyl, C2-6alkenyl, C1-3perfluoroalkyl-, C1-3perfluoroalkoxy, aryl, arylC1-6alkyl, heterocyclyl, heterocyclylC1-6alkyl, aminoC0-4alkyl, N—C1-4alkylaminoC0-4alkyl, N,N-di-C1-4alkylaminoC0-4alkyl, carbamoyl, N—C1-4alkylcarbamoylC0-2alkyl, N,N-di-C1-4alkylaminocarbamoylC0-2alkyl, aminocarbonylC0-4alkyl, N—C1-6alkyaminocarbonylC1-4alkyl, N,N-C1-6alkyaminocarbonylC0-4alkyl, C1-6alkyl-S(O)n-aminoC0-4alkyl-, aryl-S(O)n-aminoC0-2alkyl-, C1-3perfluoroalkyl-S(O)n-aminoC0-2alkyl-;
• C1-6alkylamino-S(O)n—C0-2alkyl-, arylamino-S(O)n—C0-2alkyl-, C1-3perfluoroalkylamino-S(O)n—C0-2alkyl-, C1-6alkanoylamino-S(O)n—C0-2alkyl-;
• arylcarbonylamino-S(O)n—C0-2alkyl-, C1-6alkyl-S(O)n—C0-2alkyl-, aryl-S(O)n—C0-2alkyl- , C1-3perfluoroalkyl-, C1-3perfluoroalkoxyC0-2alkyl;
• R9′OC(O)(CH2)w—, R9″R10″N(CH2)w—, R9′R10′NC(O)(CH2)w—, R9R10NC(O)N(R9)(CH2)w—, R9OC(O)N(R9)(CH2)w—, or halo, wherein w is an integer between 0 and 4 and R9 and R10 are independently selected from hydrogen, C1-4alkyl, C1-4alkylsulphonyl and C3-7carbocyclyl, R9′ and R10′ are independently selected from C1-4alkylsulphonyl and C3-7carbocyclyl, and R9″ and R10″ are C3-7carbocyclyl;
• wherein an amino or an aryl group within R12 is optionally substituted by C1-4alkyl;
• R13 is C1-4alkylaminocarbonyl optionally substituted by 1, 2 or 3 groups selected from R12, or R13 is a group —C(O)—R16 where R16 is selected from an amino acid derivative or an amide of an amino acid derivative;
• A is selected from:
• (i) a direct bond;
• (ii) optionally substituted C1-5alkylene wherein the optional substituents are independently selected from:
• hydroxy, hydroxyC1-6alkyl, C1-6alkyl, C1-6alkoxy, C1-4alkoxyC1-4alkyl, aryl or arylC1-6alkyl;
• (iii) a carbocyclic ring of 3-7 atoms;
• (iv) a carbonyl group or —C(O)—C(RdRd)—, wherein Rd is independently selected from hydrogen and C1-2alkyl;
• or when R3 is a group of Formula (IIa) or (IIb), the group
• forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms;
• or when R3 is a group of Formula (IIa), (IIb), (IIc) or (IId), the group
• forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms;
• B is selected from:
• (i) a direct bond;
• (ii) a group of Formula (IV)
• wherein:
• X is selected from N or CH,
• wherein at position (a) Formula (IV) is attached to the nitrogen atom and the (CH2)p group is attached to R8;
• and
• (iii) a group independently selected from:
• optionally substituted C1-6alkylene, optionally substituted C3-7cycloalkyl, optionally substituted C3-6alkenylene, optionally substituted C3-6alkynyl, (C1-5alkyl)aa-S(On)—(C1-5alkyl)bb-, —(C1-5alkyl)aa-O—(C1-5alkyl)bb-, —(C1-5alkyl)aa-C(O)—(C1-5alkyl)bb- or (C1-5alkyl)aa-N(R14)—(C1-5alkyl)bb, or (C1-5alkyl)aa-C(O)N(R14)—(C1-5alkyl)bb, wherein R14 is hydrogen or C1-4alkyl, or R14 and the (C1-5alkyl)aa or (C1-5alkyl)bb chain can be joined to form a heterocyclic ring, wherein aa and bb are independently 0 or 1, and the combined length of (C1-5alkyl)aa and (C1-5alkyl)bb is less than or equal to C5alkyl and wherein the optional substituents are independently selected from R12;
• or the group —B—R8 represents a group of Formula (V)
• or the group
• together forms an optionally substituted heterocyclic ring containing 4-7 carbons atoms, wherein the optional substituents are selected from 1 or 2 substituents independently selected from R12 and R13;
• or the group
• forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms;
• R11 is selected from:
• hydrogen, optionally substituted C1-6alkyl or N(R23R24);
• R23 and R24 are independently selected from:
• hydrogen, hydroxy, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted arylC1-6alkyl, an optionally substituted carbocyclic ring of 3-7 atoms, optionally substituted heterocyclyl, optionally substituted heterocyclylC1-6alkyl or R23 and R24 taken together can form an optionally substituted ring of 3-9 atoms, wherein the optional substituents are selected from R12 and
• J is a group of the formula:
• —(CH2)s-L-(CH2)s— or —(CH2)s—C(O)—(CH2)s-L-(CH2)s— wherein when s is greater than 0, the alkylene group is optionally substituted by 1 or 2 groups selected from R12,
• or the group
• together forms an optionally substituted heterocyclic ring containing 4-7 carbons atoms, wherein the optional substituents are selected from 1 or 2 substituents independently selected from R12 and R13;
• K is selected from:
• a direct bond, —(CR21R22)s1—, —(CR21R22)s1—O—(CR21R22)s2—, —(CR21R22)s1—C(O—(CR21R22)s2—, —(CR21R22)s1—S(O)n—(CR21R22)s2—, —(CR21R22)s1—N(R14a)—(CR21R22)s2—, —(CR21R22)s1—C(O)N(R14a)—(CR21R22)s2—, —(CR21R22)s1—N(R14a)C(O)—(CR21R22)s2—, —(CR21R22)s1—N(R14a)C(O)N(R14a)—(CR21R22)s2—, —(CR21R22)s1—OC(O)—(CR21R22)s2—, —(CR21R22)s1—C(O)O—(CR21R22)s2—, —(CR21R22)s1—N(R14a)C(O)O—(CR21R22)s2, —(CR21R22)s1—OC(O)N(R14a)—(CR21R22)s2—, —(CR21R22)s1—OS(On)—(CR21R22)s2, or —(CR21R22)s1—S(On)—O—(CR21R22)s2—, —(CR21R22)s1—S(O)2N(R14a)—(CR21R22)s2— or —(CR21R22)s1—N(R14a)S(O)2—(CR21R22)s2—;
• wherein
• R14a is hydrogen or C1-4alkyl, each R21and R22 group is independently selected from hydrogen, hydroxy or optionally substituted C1-4alkyl, wherein the optional substituent is a group ZR30 where Z is oxygen or a group S(O)n, and R30 is hydrogen or C1-4alkyl;
• L is selected from optionally substituted aryl or optionally substituted heterocyclyl;
• n is an integer from 0 to 2;
• p is an integer from 0 to 4;
• s, s1 and s2 are independently selected from an integer from 0 to 4, and
• s1+s2 is less than or equal to 4;
• or a salt, solvate or pro-drug thereof.