Thienopyrroles as antagonists of gnrh

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, nitro, cyano, fluoro and C1-4alkoxy;
• 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 selected from a group of Formula III-a;
• III-b;
• III-c;
• III-d;
• III-e;
• III-f, III-g, III-h, III-i, or III-j, III-k, III-l, III-m, III-n, III-o or III-p
• wherein:
• het represents an optionally substituted 3- to 8-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from O, N and S, wherein the optional substituents are selected from 1-2 groups selected from R12 and R13;
• R14 and R15 are selected from:
• (i) R14 is selected from hydrogen;
• optionally substituted C1-8alkyl;
• optionally substituted aryl;
• —Rd—Ar, where Rd represents C1-8alkylene and Ar represents optionally substituted aryl;
• and optionally substituted 3- to 8-membered heterocyclic ring optionally containing from 1 to 3 further heteroatoms independently selected from I, N and S;
• and R15 is selected from hydrogen;
• optionally substituted C1-8alkyl and optionally substituted aryl;
• (ii) when R5 represents a group of Formula III-a, III-b, III-i, III-l or III-m, then the group NR14(—R15) additionally represents an optionally substituted 3- to 8-membered heterocyclic ring optionally containing from 1 to 3 further heteroatoms independently selected from O, N and S;
• or
• (iii) when R5 represents structure III-e,
• represents an optionally substituted 3- to 8-membered heterocyclic ring optionally containing from 1 to 4 heteroatoms independently selected from O, N and S;
• R20 and R20a are independently selected from hydrogen, fluoro or optionally substituted C1-8alkyl, or R20 and R20a together with the carbon atom to which they are attached form an optionally substituted 3 to 7-membered cycloalkyl ring;
• 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-C1-6alkyaminocarbonylC0-4alkyl, N,N-C1-6alkyaminocarbonylC0-4alkyl, C1-6alkyl-S(O)n-aminoC0-4alkyl-, aryl-S(O)n-aminoC0-2alkyl-, C1-3perfluoroalkyl-S(O)n-aminoC-0-2alkyl-;
• 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 —C(O)—R16;
• R16 is selected from an amino acid derivative or an amide of an amino acid derivative;
• R17 is hydrogen or C1-4alkyl;
• 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, arylC1-6alkyl, carbonyl or carbonylmethyl;
• (iii) a carbocyclic ring of 3-7 atoms;
• (iv) a carbonyl group or —C(O)—C(RdRd)—, wherein each 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 wherein R11 is selected from hydrogen, optionally substituted C1-6alkyl or N(R23R24),
• where 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 for any optionally substituted group R23, R24 and C1-6alkyl groups R11 are selected from R12 and
• where K and R8 are as defined herein;
• (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(R14a)-(C1-5alkyl)bb, or —(C1-5alkyl)aa-C(O)NR14a—(C1-5alkyl)bb-
• wherein R14a is a group R14 as defined above, or R14a 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;
• 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 to 2 group 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(R17)—(CR21R22)s2—, —(CR21R22)s1—C(O)N(R17)—(CR21R22)s2—, —(CR21R22)s1—N(R17)C(O)—(CR21R22)s2—, —(CR21R22)s1—N(R17)C(O)N(R17)—(CR21R22)s2—, —(CR21R22)s1—OC(O)—(CR21R22)s2—, —(CR21R22)s1—C(O)O—(CR21R22)s2—, —(CR21R22)s1—N(R17)C(O)O—(CR21R22)s2, —(CR21R22)s1—OC(O)N(R17)—(CR21R22)s2—, —(CR21R22)s1—OS(On)—(CR21R22)s2, or —(CR21R22)s1—S(On)—O—(CR21R22)s2—, —(C21R22)s1—S(O)2N(R17)—(CR21R22)s2— or —(CR21R22)s1—N(R17)S(O)2—(CR21R22)s2—;
• wherein each R21 and 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 where n is as described above, 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;
• with the proviso that the compound must contain at least one of the following groups:
• (i) R3 is a group of formula (IIc) or (IId) wherein J is a group of the formula:
• —(CH2)s—C(O)—(CH2)s-L-(CH2)s-, and/or
• (ii) R2 is selected from hydrogen or optionally substituted C1-6alkyl, and/or
• (iii) at least one group R6 or R6a is selected from C1-6alkoxy, N-C1-6alkylamino and N,N-diC1-6alkylamino, and/or
• (iv) R5 is a group of formula III-k, III-I, III-o or III-p, and/or
• (v) R8 is selected from substituted C3-7cycloalkyl, substituted aryl or substituted arylC1-6alkyl, wherein a substituent is a group R13;
• or R8 is a heterocyclyl or heterocyclylC1-6alkyl each of which is substituted by a group R13 and optionally by up to 3 further substituents independently selected from R12 or R13;
• and/or
• (vi) both of R21 and R22 within a —(CR21R22)s1— or —(CR21R22)s2— are C1-4alkyl;
• or
• (vii) at least one of R21 or R22 within a —(CR21R22)s1— or —(CR21R22)s2— is a C1-4alkyl which is optionally substituted by a group ZR30,
• or a salt, solvate or pro-drug thereof.