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US 2007/0185106 A1Published application
Pyrrole derivatives as gonadotropin releasing hormone (gnrh) antagonists
AssigneeAstraZeneca AB
InventorCraig Harris
Life of this patent
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Abstract
The invention relates to a group of novel thieno-pyrrole compounds of formula (I) wherein: R1, R2, R3, R4 M, and R5 are as defined in the specification, as inter alia, gonadotrophin releasing hormone antagonists. Novel compounds of formula (I) are also claimed. The invention also relates to pharmaceutical formulations of said compounds, methods of treatment using said compounds and to processes for the preparation of said compounds.
Claims17
A method of antagonising gonadotropin releasing hormone activity in a patient, comprising administering 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 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):
- where R6 and R6a are independently selected from hydrogen, fluoro, optionally substituted C1-6alkyl, C1-6alkoxy, 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 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;
- 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(R17)—(C1-5alkyl)bb, or —(C1-5alkyl)aa-C(O)NH—(C1-5alkyl)bb-
- where R17 is hydrogen or C1-4alkyl, or where R17 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 C1-5alkyl 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, N(R23R24) or NC(O)OR25, where R23, R24 and R25 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 or optionally substituted heterocyclylC1-6alkyl or R23 and R24 taken together with the nitrogen atom to which they are attached, can form an optionally substituted ring of 3-10 atoms, wherein the optional substituents are selected from R12 and
- where K and R8 are as defined herein;
- 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,
- 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, —(CH2)s1—, —(CH2)s1—O—(CH2)s2—, —(CH2)s1—C(O)—(CH2)s2—, —(CH2)s1—S(On)—(CH2)s2—, —(CH2)s1—N(R17a)—(CH2)s2—, —(CH2)s1—C(O)N(R17a)—(CH2)s2—, —(CH2)s1—N(R17a)C(O)—(CH2)s2—, —(CH2)s1—N(R17a)C(O)N(R17a)—(CH2)s2—, —(CH2)s1—OC(O)—(CH2)s2—, —(CH2)s1—C(O)O—(CH2)s2—, —(CH2)s1—N(R17a)C(O)O—(CH2)s2—, —(CH2)s1—OC(O)N(R17a)—(CH2)s2—, —(CH2)s1—OS(On)—(CH2)s2—, or —(CH2)s1—S(On)—O—(CH2)s2—, —(CH2)s1—S(O)2N(R17a)—(CH2)s2— or —(CH2)s1—N(R17a)S(O)2—(CH2)s2—;
- wherein the —(CH2)s1— and —(CH2)s2— groups are independently optionally substituted by hydroxy or C1-4alkyl and wherein when s1>1 or s2>1 then the CH2 group can optionally be a branched chain;
- where R17a is hydrogen or C1-4alkyl;
- L is selected from optionally substituted aryl or optionally substituted heterocyclyl;
- 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 or III-o
- 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;
- and
- Q is selected from a direct bond or —[C(R16R16a)]1-2—;
- R14 and R15 are selected from:
- (i) R14 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 O, N and S;
- and R15 is selected from hydrogen;
- optionally substituted C1-8alkyl and optionally substituted aryl;
- (ii) wherein the group of Formula (III) represents a group of Formula III-a, III-b, III-i, III-l or III-m, then the group NR14(—R15) 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) wherein the group of Formula (III) 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;
- R16 and R16a are independently selected from:
- (i) hydrogen or optionally substituted C1-8alkyl;
- or
- (ii) R16 and R16a together with the carbon to which they are attached form an optionally substituted 3 to 7-membered cycloalkyl ring;
- 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-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 group within R12 is optionally substituted by C1-4alkyl;
- R13 is C1-4alkylaminocarbonyl wherein the alkyl group is optionally substituted by 1, 2 or 3 groups selected from R12, or R13 is a group —C(O)—R18 and R18 is selected from an amino acid derivative or an amide of an amino acid derivative;
- M is selected from —CH2—CH2— or —CH═CH—;
- 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;
- t is an integer between 0 and 4;
- and
- or a salt, solvate or pro-drug thereof to a patient.
96 more elements
A compound of formula (IA) which is 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 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):
- where R6 and R6a are independently selected from hydrogen, fluoro, optionally substituted C1-6alkyl, C1-6alkoxy, 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 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;
- 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 C1-7cycloalkyl 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(R17)—(C1-5alkyl)bb, or —(C1-5alkyl)aa-C(O)NH—(C1-5alkyl)bb-
- where R17 is hydrogen or C1-4alkyl, or where R17 and the (C1-5alkyl)aa or (C1-15alkyl)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 N(R23R24) or NC(O)OR25 where R23, R24 and R25 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 or optionally substituted heterocyclylC1-6alkyl or R23 and R24 taken together with the nitrogen atom to which they are attached, can form an optionally substituted ring of 3-10 atoms, wherein the optional substituents are selected from R12 and
- where K and R8 are as defined herein;
- 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,
- 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, —(CH2)s1—, —(CH2)s1—O—(CH2)s1—C(O)—(CH2)s2, —(CH2)s1—S(On)—(CH2)s2—, —(CH2)s1—N(R17a)—(CH2)s2, —(CH2)s1—C(O)N(R17a)—(CH2)s2, —(CH2)s1—N(R17a)C(O)—(CH2)s2—, —(CH2)s1—N(R17a)C(O)N(R17a)—(CH2)s2—, —(CH2)s1—OC(O)—(CH2)s2—, —(CH2)s1—C(O)O—(CH2)s2—, —(CH2)s1—N(R17a)C(O)O—(CH2)s2—, —(CH2)s1—OC(O)N(R17a)—(CH2)s2—, —(CH2)s1—OS(On)—(CH2)s2—, or —(CH2)s1—S(On)—O—(CH2)s2—, —(CH2)s1—S(O)2N(R17a)—(CH2)s2— or —(CH2)s1—N(R17a)S(O)2—(CH2)s2—;
- wherein the —(CH2)s1— and —(CH2)s2— groups are independently optionally substituted by hydroxy or C1-4alkyl and wherein when s1>1 or s2>1 then the CH2 group can optionally be a branched chain;
- where R17a is hydrogen or C1-4alkyl;
- L is selected from optionally substituted aryl or optionally substituted heterocyclyl;
- 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 or III-o
- 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;
- and
- Q is selected from a direct bond or —[C(R16R16a)]1-2—;
- R14 and R15 are selected from:
- (i) R14 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 O, N and S;
- and R15 is selected from hydrogen;
- optionally substituted C1-8alkyl and optionally substituted aryl;
- (ii) wherein the group of Formula (III) represents a group of Formula III-a, III-b, III-i, III-l or III-m, then the group NR14(—R15) 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) wherein the group of Formula (III) 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;
- R16 and R16a are independently selected from:
- (i) hydrogen or optionally substituted C1-8alkyl;
- or
- (ii) R16 and R16a together with the carbon to which they are attached form an optionally substituted 3 to 7-membered cycloalkyl ring;
- R12 is independently selected from:
- halo, hydroxy, hydroxyC1-6alkyl, oxo, cyano, cyanoC1-6alkyl, nitro, carboxyl, C1-6alkyl, C1-6alkoxyC1-6alkoxyC1-4alkyl, 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-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 group within R12 is optionally substituted by C1-4alkyl;
- R13 is C1-4alkylaminocarbonyl wherein the alkyl group is optionally substituted by 1, 2 or 3 groups selected from R12 or R13 is a group —C(O)—R18 and R18 is selected from an amino acid derivative or an amide of an amino acid derivative;
- M is selected from —CH2—CH2— or —CH═CH—;
- 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;
- t is an integer between 0 and 4;
- and
- or a salt solvate or pro-drug thereof;
- with the proviso that when
- (i) the group
- forms an aromatic carbocyclic ring of 3-7 carbon atoms or an aromatic heterocyclic ring containing one or more heteroatoms, or
- (ii) when R3 is a group of Formula (IIa) or (IIb), and the group
- forms an aromatic heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms;
- or
- (iii) when R3 is a group of Formula (IIa), (IIb), (IIc) or (IId), and the group
- forms an aromatic heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms, or
- (iv) when the group
- forms an aromatic heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms and A is a direct bond;
- then R5 is other than a group III-o.
107 more elements
A compound selected from:
- 3-[3,3-dimethyl-4-oxo-4-(azabicyclo[2.2.1]heptan-7-yl)butyl]-4-[2-{4-(morpholin-4-ylcarbonyl)piperidin-1-yl}ethyl]-5-(3,5-dimethylphenyl)-1H-pyrrole;
- 3-[3,3-dimethyl-4-oxo-4-(azabicyclo[2.2.1]heptan-7-yl)but-2-en-1-yl]-4-[1s-methyl-2-(n′-isopropoxycarbonyl-3-pyrid-4-yl-pyrrolidin-1-ylcarboximidamido)ethyl]-5-(3,5-dimethylphenyl)-1h-pyrrole;
- 3-[3,3-dimethyl-4-oxo-4-(azabicyclo[2.2.1]heptan-7-yl)butyl]-4-[1S-methyl-2-(N′-isopropoxycarbonyl-3-pyrid-4-yl-pyrrolidin-1-ylcarboximidamido)ethyl]-5-(3,5-dimethylphenyl)-1H-pyrrole;
- 3-[3,3-dimethyl-4-oxo-4-(azabicyclo[2.2.1]heptan-7-yl)butyl]-4-[2-{4-(pyrrolidin-1-ylcarbonyl)piperazin-1-yl}ethyl]-5-(3,5-dimethylphenyl)-1H-pyrrole;
- 2-chloro-3-[3,3-dimethyl-4-oxo-4-(azabicyclo[2.2.1]heptan-7-yl)butyl]-4-[2-{4-(pyrrolidin-1-ylcarbonyl)piperazin-1-yl}ethyl]-5-(3,5-dimethylphenyl)-1h-pyrrole;
- 3-[3,3-dimethyl-4-oxo-4-(azabicyclo[2.2.1]heptan-7-yl)butyl]-4-[2-{4-(4-hydroxypiperidin-1-ylcarbonyl)piperidin-1-yl}ethyl]-5-(3,5-dimethylphenyl)-1h-pyrrole;
- 3-[3,3-dimethyl-4-oxo-4-(azabicyclo[2.2.1]heptan-7-yl)butyl]-4-[2-{4-(1,1-dioxo-isothiazolidin-2-ylcarbonyl)-4-methoxy-piperidin-1-yl}ethyl]-5-(3,5-dimethylphenyl)-1h -pyrrole;
- 3-[3,3-dimethyl-4-oxo-4-(azabicyclo[2.2.1]heptan-7-yl)butyl]-4-[1s-methyl-2-{1-benzyl-pyrrodin-3-ylamino}ethyl]-5-(3,5-dimethylphenyl)-1h-pyrrole;
- 3-[3,3-dimethyl-4-oxo-4-(azabicyclo[2.2.1]heptan-7-yl)butyl]-4-[1s-methyl-2-(2-{4-n-isopropylureidophenyl}ethylamino)ethyl]-5-(3,5-dimethylphenyl)-1h-pyrrole;
- 3-[3,3-dimethyl-4-oxo-4-(azabicyclo[2.2.1]heptan-7-yl)butyl]-4-[1s-methyl-2-{4-(pyrid-4-yl)piperidin-1-ylcarbonylamino}ethyl]-5-(3,5-dimethylphenyl)-1h-pyrrole;
- 3-[3,3-dimethyl-4-oxo-4-(azabicyclo[2.2.1]heptan-7-yl)butyl]-4-[1s-methyl-2-{3-(pyrid-4-yl)pyrrolidin-1-ylcarbonylamino}ethyl]-5-(3,5-dimethylphenyl)-1h-pyrrole;
- and
- 3-[3,3-dimethyl-4-oxo-4-(azabicyclo[2.2.1]heptan-7-yl)butyl]-4-[1s-methyl-2-{4-phenylpiperidin-1-ylcarbonylamino}ethyl]-5-(3,5-dimethylphenyl)-1h-pyrrole.
10 more elements
17-18. (canceled)
Dependencies are inferred from the claim text.