6H-THIENO[2,3-b]PYRROLE DERIVATIVES AS ANTAGONISTS OF GONADOTROPIN RELEASING HORMONE (GNRH)

A compound of Formula (I),

• wherein
• R1 is selected from:
• hydrogen, optionally-substituted C1-6alkyl, optionally substituted C1-6alkanoyl, optionally substituted aryl or optionally-substituted arylC1-6alkyl;
• R2 is an optionally-substituted mono or bi-cyclic aromatic ring;
• R3 is selected from a group of Formula (IId):
• R4 is selected from:
• hydrogen, optionally substituted C1-6alkyl, optionally substituted aryl, C1-3perfluoroalkyl, cyano, nitro, halo, R9O(CH2)m—, R9C(O)N(R10)—, R9R10NC(O)N(R10)(CH2)m—R9S(On)(CH2)m— or R9R10NC(O)—(CR9R10)t(CH2)m—;
• R5 is a group of Formula (III):
• R6 and R6a are independently selected from hydrogen, fluoro, optionally substituted C1-6alkyl, optionally-substituted aryl or optionally substituted arylC1-6alkyl, 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;
• R7 is selected from:
• hydrogen, optionally-substituted C1-6alkyl, optionally-substituted arylC1-6alkyl, optionally-substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclylC1-6alkyl, R9OC1-6alkyl-, R9R10NC1-6alkyl-, R9R10NC(O)C1-6alkyl, —C(NR9R10)═NH;
• or R7 is of the formula -J-K—R8;
• 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 C1-4alkyl 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) C3-7cycloalkyl, aryl or arylC1-6alkyl each of which is optionally substituted by R12, R13 and R14;
• (ii) -(Q)-aryl, -(Q)-heterocyclyl, -aryl-(Q)-aryl, each of which is optionally substituted by R12, R13 and R14
• wherein -(Q)- is selected from E, F or a direct bond;
• (iv) heterocyclyl or heterocyclylC1-6alkyl each of which is optionally substituted by up to 4 substituents independently selected from R12, R13 and R14;
• (v) a group selected from R12, R13 and R14;
• R9 and R10 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 R9 and R10 taken together can form an optionally substituted ring of 3-9 atoms or R9 and R10 taken together with the carbon atom to which they are attached form a carbonyl group;
• R12 is selected from:
• hydrogen, hydroxy, R17R18N(CH2)cc—, R17R18NC(O)(CH2)cc—, optionally substituted C1-6alkyl-C(O)N(R9)(CH2)cc—, optionally substituted C1-6alkyl-SO2N(R9)—, optionally substituted aryl-SO2N(R9)—, C1-3perfluoroalkyl-SO2N(R9)—;
• optionally substituted C1-6alkyl-N(R9)SO2—, optionally substituted aryl-N(R9)SO2—, C1-3perfluoroalkyl-N(R9)SO2— optionally substituted C1-6alkanoyl-N(R9)SO2—;
• optionally substituted aryl-C(O)N(R9)SO2—, optionally substituted C1-6alkyl-S(On)—, optionally substituted aryl-S(On)—, C1-3perfluoroalkyl-, C1-3perfluoroalkoxy, optionally substituted C1-6alkoxy, carboxy, halo, nitro or cyano;
• R13 and R14 are independently selected from:
• hydrogen, hydroxy, oxo, optionally substituted C1-6alkyl, optionally substituted C1-6alkanoyl, optionally substituted C2-6alkenyl, cyano, nitro, C1-3perfluoroalkyl-, C1-3perfluoroalkoxy, optionally substituted aryl, optionally substituted arylC1-6alkyl, R9O(CH2)s—, R9(O)O(CH2)s—, R9OC(O)(CH2)s—, R16S(On)(CH2)s—, R9R10NC(O)(CH2)s— or halo;
• R15 is selected from:
• hydrogen, optionally substituted C1-6alkyl, R19OC(O)—, R9R10NC(O)—, R9C(O)—, R9S(On)—;
• R16 is selected from:
• hydrogen, C1-6alkyl, C1-3perfluoroalkyl or optionally-substituted aryl;
• R17 is independently selected from:
• hydrogen, hydroxy, cyano or optionally substituted C1-6alkyl;
• R18 is a group of formula R18a—C(R9R10)0-1— wherein R18a is selected from:
• R19OC(O)—, R9R10NC(O)—, R9R10N—, R9C(O)—, R9C(O)N(R10)—, R9R10NC(O)—, R9R10NC(O)N(R10)—, R9SO2N(R10)—, R9R10NSO2N(R10)—R9C(O)O—R9OC(O)—R9R10NC(O)O—, R9O—, R9S(On)—, R9R10NS(On)—, hydrogen, optionally substituted C1-6alkyl, optionally substituted heterocyclyl;
• or R17 and R18 when taken together form an optionally substituted carbocyclic ring of 3-7 atoms or optionally substituted heterocyclyl;
• R19 is selected from:
• hydrogen, optionally substituted C1-6alky, optionally substituted aryl, optionally substituted arylC1-6alkyl, optionally substituted C3-7cycloalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylC1-6alkyl;
• R20 is selected from R12 or R13;
• A is selected from:
• (i) a direct bond;
• (ii) optionally-substituted C1-5alkylene wherein the optional substituents are independently selected from:
• optionally-substituted C1-6alkyl optionally-substituted aryl or optionally substituted 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;
• E is —O—, —S(On), —C(O)—, —NR15— or —C(R9R10)q;
• F is -E(CH2)r— or —(CH2)rE-;
• G is selected from:
• hydrogen, halo, CN, NO2, N, O, S(On), C(O), C(R9R10)t, optionally substituted C2-6alkenylene, optionally substituted C2-6alkynylene, optionally substituted heterocyclyl or a direct bond to R18,
• J is a group of the formula:
• —(CH2)s-L-(CH2)s— wherein when s is greater than 0, the alkylene group is optionally substituted,
• or the group
• together forms an optionally substituted heterocyclic ring containing 4-7 carbons atoms;
• K is selected from:
• a direct bond, —(CH2)s1—, —(CH2)s2—O—(CH2)s—, —(CH2)s1C(O)—(CH2)s2—, —(CH2)s1—S(On)—(CH2)s2—, —(CH2)s1—N(R18)—(CH2)s2—, —(CH2)s1—C(O)N(R9)—(CH2)s2—, —(CH2)s1—N(R9)C(O)—(CH2)s2—, —(CH2)s1—N(R9)C(O)N(R9)—(CH2)s2—, —(CH2)s1—OC(O)—(CH2)s2—, —(CH2)s1—C(O)O—(CH2)s2—, —(CH2)s1—N(R9)C(O)O—(CH2)s2—, —(CH2)s1—OC(O)N(R9)—(CH2)s2—, —(CH2)s1—OS(On)—(CH2)s—, —(CH2)s1—S(On)—O—(CH2)s2—, —(CH2)s1—S(O)2N(R9)—(CH2)s2—, or —(CH2)s1—N(R9)S(O)2—(CH2)s2—;
• wherein the —(CH2)s1— and —(CH2)s2— groups are independently optionally substituted by hydroxy or C1-4alkyl;
• L is selected from optionally substituted aryl or optionally substituted heterocyclyl;
• m is an integer from 0 to 4;
• n is an integer from 0 to 2;
• q is an integer from 0 to 4;
• r is an integer from 0 to 4;
• s is an integer from 0 to 4;
• s1 and s2 are independently selected from an integer from 0 to 4, and
• s1+s2 is less than or equal to 4;
• and
• t is an integer from 0 to 4;
• cc is an integer between 0 to 2;
• with the proviso that
• (i) when G is hydrogen, halo, CN or NO2 then R17 and R18 are both absent;
• (ii) when G is O, S(On), C(O) or C(R9R10)t then G is substituted by a single group independently selected from the definition of R17 or R18 and when G is a direct bond to R18 then G is substituted by a single group selected from R18;
• or a salt, pro-drug or solvate thereof.